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WO2008023180A1 - Morpholino pyrimidine derivatives useful in the treatment of proliferative disorders - Google Patents

Morpholino pyrimidine derivatives useful in the treatment of proliferative disorders Download PDF

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WO2008023180A1
WO2008023180A1 PCT/GB2007/003211 GB2007003211W WO2008023180A1 WO 2008023180 A1 WO2008023180 A1 WO 2008023180A1 GB 2007003211 W GB2007003211 W GB 2007003211W WO 2008023180 A1 WO2008023180 A1 WO 2008023180A1
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alkyl
compound
amino
bis
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Maurice Raymond Verschoyle Finlay
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AstraZeneca UK Ltd
AstraZeneca AB
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AstraZeneca UK Ltd
AstraZeneca AB
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Priority claimed from GB0616747A external-priority patent/GB0616747D0/en
Application filed by AstraZeneca UK Ltd, AstraZeneca AB filed Critical AstraZeneca UK Ltd
Priority to US12/438,477 priority Critical patent/US20090325957A1/en
Priority to EP07789303A priority patent/EP2057129A1/en
Priority to JP2009525108A priority patent/JP2010501537A/en
Publication of WO2008023180A1 publication Critical patent/WO2008023180A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to morpholino pyrimidine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, for example in the treatment of proliferative disease such as cancer and particularly in
  • tumour-suppressor genes contributes to the formation of malignant tumours, for example by way of increased cell proliferation or increased cell survival. It is also known that signalling pathways mediated by the PBK/mTOR families have a central role in a number of cell processes io including proliferation and survival, and deregulation of these pathways is a causative factor in a wide spectrum of human cancers and other diseases.
  • the mammalian target of the macrolide antibiotic Rapamycin is the enzyme mTOR.
  • This enzymes belongs to the phosphatidylinositol (PI) kinase-related kinase (PIKK) family of protein kinases, which also includes ATM, ATR, DNA-PK and
  • mTOR like other PIKK family members, does not possess detectable lipid kinase activity, but instead functions as a serine/threonine kinase.
  • Much of the knowledge of mTOR signalling is based upon the use of Rapamycin. Rapamycin first binds to the 12 kDa immunophilin FK506-binding protein (FKBP 12) and this complex inhibits mTOR signalling (Tee and Blenis, Seminars in Cell and Developmental Biology, 2005, 16, 29-
  • the mTOR protein consists of a catalytic kinase domain, an FKBP12-Rapamycin binding (FRB) domain, a putative repressor domain near the C-terminus and up to 20 tandemly-repeated HEAT motifs at the iV-terminus, as well as FRAP-ATM-TRRAP (FAT) and FAT C-terminus domain (Huang and Houghton, Current Opinion in Pharmacology, 2003, 3, 371-377).
  • mTOR kinase is a key regulator of cell growth and has been shown to regulate a wide range of cellular functions including translation, transcription, mRNA turnover, protein stability, actin cytoskeleton reorganisation and autophagy (Jacinto and Hall, Nature Reviews Molecular and Cell Biology, 2005, 4, 117-126). mTOR kinase integrates signals from growth factors (such as insulin or insulin-like growth factor) and nutrients
  • mTOR kinase is activated by growth factors through the PI3K-Akt pathway.
  • the most well characterised function of mTOR kinase in mammalian cells is regulation of translation through two pathways, namely activation of ribosomal S6K1 to enhance translation of mRNAs that bear a 5'- terminal oligopyrimidine tract (TOP) and suppression of 4E-BP1 to allow CAP-dependent mRNA translation.
  • TOP 5'- terminal oligopyrimidine tract
  • PI3K. pathway the pathways upstream of mTOR, such as the PI3K. pathway, are frequently activated in cancer (Vivanco and Sawyers, Nature Reviews Cancer, 2002, 2, 489-501 ; Bjornsti and Houghton, Nature Reviews Cancer, 2004, 4, 335-348; Inoki et al, Nature Genetics, 2005, 37, 19-24).
  • components of the PI3K pathway that are mutated in different human tumours include activating mutations of growth factor receptors and the amplification and/or overexpression of PI3K and Akt.
  • endothelial cell proliferation may also be dependent upon mTOR signalling.
  • Endothelial cell proliferation is stimulated by vascular endothelial cell growth factor (VEGF) activation of the PI3K-Akt-mTOR signalling pathway (Dancey, Expert Opinion on Investigational Drugs, 2005, 14, 313-328).
  • VEGF vascular endothelial cell growth factor
  • mTOR kinase signalling is believed to partially control VEGF synthesis through effects on the expression of hypoxia-inducible factor- 1 ⁇ (HIF- 1 ⁇ ) (Hudson et al. , Molecular and Cellular Biology, 2002, 22, 7004-7014).
  • tumour angiogenesis may depend on mTOR kinase signalling in two ways, through hypoxia-induced synthesis of VEGF by tumour and stromal cells, and through VEGF stimulation of endothelial proliferation and survival through PI3K-Akt-mTOR signalling.
  • inhibitors of niTOR kinase should be of therapeutic value for treatment of, for example, cancer of the breast, colorectum, lung (including small cell lung cancer, non- small cell lung cancer and bronchioalveolar cancer) and prostate, and of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovaiy , pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas.
  • cancer of the breast, colorectum, lung (including small cell lung cancer, non- small cell lung cancer and bronchioalveolar cancer) and prostate and of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovaiy , pancreas, skin, testes, thyroid, uterus, cervix
  • tumour suppressor proteins such as TSCl, TSC2, PTEN and LKBl tightly control mTOR kinase signalling. Loss of these tumour suppressor proteins leads to a range of hamartoma conditions as a result of elevated mTOR kinase signalling (Tee and Blenis, Seminars in Cell and Developmental Biology, 2005, 16, 29-37).
  • Syndromes with an established molecular link to dysregulation of mTOR kinase include Koz-Jeghers syndrome (PJS), Cowden disease, Bannayan-Riley-Ruvalcaba syndrome (BRRS), Proteus syndrome, Lhermitte-Duclos disease and Tuberous Sclerosis (TSC) (Inoki et al, Nature Genetics, 2005, 37, 19-24). Patients with these syndromes characteristically develop benign hamartomatous tumours in multiple organs.
  • Rapamycin has been demonstrated to be a potent immunosuppressant by inhibiting antigen-induced proliferation of T cells, B cells and antibody production (Sehgal, Transplantation Proceedings, 2003, 35, 7S-14S) and thus mTOR kinase inhibitors may also be useful immunosuppressives.
  • Inhibition of the kinase activity of mTOR may also be useful in the prevention of restenosis, that is the control of undesired proliferation of normal cells in the vasculature in response to the introduction of stents in the treatment of vasculature disease (Morice et al, New England Journal of Medicine, 2002, 346, 1773-1780).
  • the Rapamycin analogue, everolimus can reduce the severity and incidence of cardiac allograft vasculopathy (Eisen et al. New England Journal of Medicine, 2003, 349, 847- 858).
  • mTOR kinase inhibitors are expected to be of value in the prevention and treatment of a wide variety of diseases in addition to cancer.
  • PI 3-kinases Phosphatidylinositol (PI) 3-kinases (PDKs) are ubiquitous lipid kinases that function both as signal transducers downstream of cell-surface receptors and in constitutive intracellular membrane and protein trafficking pathways. All PBKs are dual- specificity enzymes with a lipid kinase activity that phosphorylates phosphoinositides at the 3-hydroxy position, and a less well characterised protein kinase activity.
  • PI3K-catalysed reactions comprising phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P 3 ], phosphatidylinositol 3,4-bisphosphate [PI(3,4)P 2 ] and phosphatidylinositol 3 -monophosphate [PI(3)P] constitute second messengers in a variety of signal transduction pathways, including those essential to cell proliferation, adhesion, survival, cytoskeletal rearrangement and vesicle trafficking.
  • PI(3)P is constitutively present in all cells and its levels do not change dramatically following agonist stimulation.
  • PI(3,4)P 2 and PI(3,4,5)P 3 are nominally absent in most cells but they rapidly accumulate on agonist stimulation.
  • PI3K-produced 3-phosphoinositide second messengers are mediated by target molecules containing 3-phosphoinositide binding domains such as the pleckstrin homology (PH) domain and the recently identified FYVE and phox domains.
  • PH pleckstrin homology
  • Well-characterised protein targets for PI3K include PDKl and protein kinase B (PKB).
  • PPKB protein kinase B
  • tyrosine kinases like Btk and Itk are dependent on PI3K activity.
  • the PI3K family of lipid kinases can be classified into three groups according to their physiological substrate specificity (Vanhaesebroeck et al , Trends in Biol. Sci., 1997, 22, 267).
  • Class III PI3K enzymes phosphorylate PI alone.
  • Class II PI3K enzymes phosphorylate both PI and PI 4-phosphate [PI(4)P].
  • Class I PI3K enzymes phosphorylate PI, PI(4)P and PI 4,5-bisphosphate [PI(4,5)P 2 ], although only PI(4,5)P 2 is believed to be the physiological cellular substrate. Phosphorylation of PI(4,5)P 2 produces the lipid second messenger PI(3,4,5)P 3 .
  • Class IV kinases such as mTOR (discussed above) and DNA-dependent kinase that phosphorylate serine/tlireonine residues within protein substrates.
  • mTOR DNA-dependent kinase that phosphorylate serine/tlireonine residues within protein substrates.
  • PI3K lipid kinases The most studied and understood of the PI3K lipid kinases are the Class I PI3K enzymes.
  • Class I PI3Ks are heterodimers consisting of a pi 10 catalytic subunit and a regulatory subunit.
  • the family is further divided into Class Ia and Class Ib enzymes on the basis of regulatory partners and the mechanism of regulation.
  • Class Ia enzymes consist of three distinct catalytic subunits (pi 10a, pi lO ⁇ and pi lO ⁇ ) that dimerise with five distinct regulatory subunits (p85 ⁇ , p55 ⁇ , p50 ⁇ , p85 ⁇ and p55 ⁇ ), with all catalytic subunits being able to interact with all regulatory subunits to form a variety of heterodimers.
  • Class Ia PBKs are generally activated in response to growth factor- stimulation of receptor tyrosine kinases via interaction of their regulatory subunit SH2 domains with specific phospho-tyrosine residues of activated receptor or adaptor proteins such as IRS-I .
  • Both pi 10a and pi lO ⁇ are constitutively expressed in all cell types, whereas pi lO ⁇ expression is more restricted to leukocyte populations and some epithelial cells.
  • the single Class Ib enzyme consists of a pi lO ⁇ catalytic subunit that interacts with a pi 01 regulatory subunit.
  • GPCRs G-protein coupled receptor systems
  • Class Ia PI3K enzymes contribute to tumourigenesis in a wide variety of human cancers, either directly or indirectly (Vivanco and Sawyers, Nature Reviews Cancer, 2002, 2, 489-501).
  • the pi 10a subunit is amplified in some tumours such as those of the ovary (Shayesteh et al. Nature Genetics, 1999, 21, 99-102) and cervix (Ma et al, Oncogene, 2000, 19, 2739-2744).
  • Class Ia PI3Ks contributes to tumourigenic events that occur upstream in signalling pathways, for example by way of ligand-dependent or ligand-independent activation of receptor tyrosine kinases, GPCR systems or integrins (Vara et al, Cancer Treatment Reviews, 2004, 30, 193-204).
  • upstream signalling pathways examples include over-expression of the receptor tyrosine kinase erbB2 in a variety of tumours leading to activation of PI3K- mediated pathways (Harari et ah, Oncogene, 2000, 19, 6102-6114) and over-expression of the ras oncogene (Kauffmann-Zeh et ⁇ /., Nature, 1997, 385, 544-548).
  • Class Ia PI3Ks may contribute indirectly to tumourigenesis caused by various downstream signalling events.
  • loss of the effect of the PTEN tumour-suppressor phosphatase that catalyses conversion of PI(3,4,5)P 3 back to PI(4,5)P 2 is associated with a very broad range of tumours via deregulation of PI3 K- mediated production of PI(3,4,5)P 3 (Simpson and Parsons, Exp. Cell Res., 2001, 264, 29-41).
  • augmentation of the effects of other PI3K-mediated signalling events is believed to contribute to a variety of cancers, for example by activation of Akt (Nicholson and Anderson, Cellular Signalling, 2002, 14, 381-395).
  • Class Ia PI3K enzymes contribute to tumourigenesis in tumour-associated stromal cells.
  • PI3K signalling is known to play an important role in mediating angiogenic events in endothelial cells in response to pro- angiogenic factors such as VEGF (Abid et ah, Arterioscler. Tliromb. Vase. Biol., 2004, 24, 294-300).
  • pro- angiogenic factors such as VEGF (Abid et ah, Arterioscler. Tliromb. Vase. Biol., 2004, 24, 294-300).
  • VEGF Ad et ah, Arterioscler. Tliromb. Vase. Biol., 2004, 24, 294-300
  • VEGF Ad et ah, Arterioscler. Tliromb. Vase. Biol., 2004, 24, 294-300
  • VEGF Ad et ah, Arterioscler. Tliromb
  • inhibitors of Class I PI3K enzymes should be of therapeutic value for treatment of, for example, cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate, and of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas.
  • cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate and of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva,
  • POK ⁇ the Class Ib PI3K
  • GPCRs GPCRs
  • neutrophils and macrophages derived from PDK ⁇ - deficient animals failed to produce PI(3,4,5)P 3 in response to stimulation with various chemotactic substances (such as IL-8, C5a, fMLP and MIP-Ia), whereas signalling through protein tyrosine kinase-coupled receptors to Class Ia PI3Ks was intact (Hirsch et al, Science, 2000, 287(5455), 1049-1053; Li et al, Science, 2002, 287(5455), 1046-1049; Sasaki et al., Science 2002, 287(5455), 1040-1046).
  • PI(3,4,5)P 3 -mediated phosphorylation of PKB was not initiated by these GPCR ligands in PI3K ⁇ -null cells.
  • murine bone marrow-derived neutrophils and peritoneal macrophages from wild- type and POK ⁇ "7" mice were tested in vitro, a reduced, but not completely abrogated, performance in chemotaxis and adherence assays was observed.
  • Inhibition of PI3K is also useful to treat cardiovascular disease via anti-inflammatory effects or directly by affecting cardiac myocytes (Prasad et al, , Trends in Cardiovascular Medicine, 2003, 13, 206-212).
  • inhibitors of Class I PI3K enzymes are expected to be of value in the prevention and treatment of a wide variety of diseases in addition to cancer.
  • PI3Ks phosphatidylinositol (PI) kinase-related kinase
  • PBKKs phosphatidylinositol kinase-related kinase
  • mTOR and/or PI3K inhibitors for use in the treatment of cancer, inflammatory or obstructive airways diseases, immune or cardiovascular diseases.
  • Morpholino pyrimidine derivatives and PI3K inhibitors are known in the art.
  • International Patent Application WO 2004/048365 discloses compounds that possess PI3K enzyme inhibitory activity and are useful in the treatment of cancer. These compounds are arylamino- and heteroarylamino-substituted pyrimidines which differ from the compounds of the present invention with respect to their aiy lamino- and heteroarylamino substituents. These substituents are not equivalent to the -XR 1 substituents of the present invention.
  • Inhibitors of PI3K activity useful in the treatment of cancer are also disclosed in European Patent Application 1 277 738 which mentions 4- morpholino-substituted bicyclic heteroaryl compounds such as quinazoline and pyrido [3 ,2-d] pyrimidine derivatives and 4-morpholino-substituted tricyclic heteroaryl compounds but not monocyclic pyrimidine derivatives.
  • the therapeutic usefulness of the derivatives is derived from their inhibitory activity against mTOR kinase and/or one or more PI3K enzyme (such as the Class Ia enzyme and/or the Class Ib enzyme). Because signalling pathways mediated by the PI3K/mTOR families have a central role in a number of cell processes including proliferation and survival, and because deregulation of these pathways is a causative factor in a wide spectrum of human cancers and other diseases, it is expected that the derivatives will be therapeutically useful. In particular, it is expected that the derivatives will have antiproliferative and/or apoptotic properties which means that they will be useful in the treatement of proliferative disease such as cancer.
  • the compounds of the present invention may also be useful in inhibiting the uncontrolled cellular proliferation which arises from various non-malignant diseases such as inflammatory diseases, obstructive airways diseases, immune diseases or cardiovascular diseases.
  • the compounds of the present invention possess potent inhibitory activity against mTOR kinase but the compound may also possess potent inhibitory activity against one or more PDK enzyme (such as the Class Ia enzyme and/or the Class Ib enzyme).
  • R 1 is a group selected from hydrogen, Ci- ⁇ alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, carbocyclylCi- 6 alkyl, heterocyclyl and heterocyclylCi -6 alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R 9 , -OR , -SR 9 , -SOR 9 , -SO 2 R 9 , -COR 9 , -CO 2 R 9 , -CONR 9 R 10 , -NR 9 R 10 , -NR 9 COR 10 , -NR 9 CO 2 R 10 , -NR 9 CONR 10 R 15 , -NR 9 COCONR 10 R 15 and -NR 9 SO 2 R 10 ;
  • R 2 is a group selected from Ci- 6 alkyl, carbocyclyl and heterocyclyl which group is substituted by -NR 17 SO 2 R 18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , -SR 11 , -SOR 11 , -SO 2 R 1 1 , -COR 11 , -CO 2 R 11 , -CONR 11 R 12 , -NR 11 R 12 , -NR 11 COR 12 , and -NR 1 1 COCONR 12 R 16 ; each R 3 , when present, is independently selected from halo, cyano, nitro, -R 13 , -OR 13 , -SR 13 , -SOR 13 , -SO 2 R 13 , -COR 13 , -CO 2 R 13 , -CONR 13 R 14 , -NR 13 R 14 , -NR 13 COR 14 , -NR
  • R 6 and R 7 are independently selected from hydrogen, halo, cyano, nitro and Ci. 6 alkyl;
  • R 8 is selected from hydrogen, halo, cyano and Ci- 6 alkyl;
  • R 9 and R 10 are independently hydrogen or a group selected from C ⁇ aHcyl, carbocyclyl, carbocyclylC] -6 alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is optionally -U-
  • R 11 , R 12 and R 17 are independently hydrogen or a group selected from Ci -6 alkyl, carbocyclyl, carbocyclylCi. 6 alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Cugalkyl, Ci- 6 alkoxy, haloCi-galkyl, haloCi-ealkoxy, hydroxyCi. 6 alkyl, hydroxyCi- 6 alkoxy, Ci.
  • R 13 , R 14 , R 15 , R 16 and R 18 are independently hydrogen or a group selected from C 1-6 alkyl, carbocyclyl, carbocyclylCi -6 alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci. 6 alkoxy, haloCi -6 alkyl, haloCi.
  • Ci alkoxy, hydroxyCi -b alkyl, hydiOxyC], 6 alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkoxy, amino, Ci -6 alkylamino, bis(Ci -6 alkyl)amino, aminoCi-ealkyl, (Ci-6alkyl)aminoCi. 6 alkyl, bis(Ci.6alkyl)aminoCi- ⁇ alkyl, cyanoCi ⁇ alkyl, Ci- ⁇ alkylsulfonyl, Ci.6alkylsulfonylamino, Ci.
  • 5 1 Y and Y 2 are independently N or CR 8 provided that one of 1 Y and Y 2 is N and the other is CR 8 ;
  • R 1 is a group selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, carbocyclylCi -6 alkyl, heterocyclyl and heterocyclylCi -6 alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R 9 , -OR 9 ,
  • R 2 is a group selected from Ci_ 6 alkyl, carbocyclyl and heterocyclyl which group is substituted by -NR 17 SO 2 R 18 and optionally substituted by one or more substituent group
  • each R 3 when present, is independently selected from halo, cyano, nitro, -R 13 , -OR 13 , -SR 13 , -SOR 11 , -SO 2 R 11 , -COR 11 , -CO 2 R 11 , -CONR 11 R 12 , -NR 11 R 12 , -NR 11 COR 12 , and -NR 11 COCONR 12 R 16 ; each R 3 , when present, is independently selected from halo, cyano, nitro, -R 13 , -OR 13 , -SR 13 , -SOR 13 , -SO 2 R 13 , -COR 13 , -CO 2 R 13 , -CONR 13 R 14 , -NR 13 R 14 , -NR 13 COR 14 , -NR 13 CO 2 R 14 and -NR 13 SO 2 R 14 ;
  • R 4 and R 5 are independently hydrogen or Ci- ⁇ alkyl; or R 1 and R 4 together with the atom or atoms to which they are attached form a 5- to 10- membered carbocyclic or heterocyclic ring wherein 1 , 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci -6 alkyl, Ci -6 alkoxy, haloCi- 6 alkyl, haloCi- ⁇ alkoxy, hydroxyCi -6 alkyl, hydroxyCi. 6 alkoxy, C ⁇ . 6 alkoxyCi..
  • Ci- b alkoxyCi -6 alkoxy amino, Ci- 6 alkylamino, bis(Ci -6 alkyl)amino, aminoCi-ealkyl, (Ci- 6 alkyl)aminoCi -0 alkyl, bis(Ci -6 alkyl)aminoCi. 6 alkyl, cyanoCi -6 alkyl, Ci- 6 alkylsulfonyl, Ci- 6 alkylsulfonylamino, Ci.
  • R 9 and R 10 are independently hydrogen or a group selected from Ci -6 alkyl, carbocyclyl, carbocyclylCi- ⁇ alkyl, heterocyclyl and heterocyclylCi. 6 alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci -6 alkyl, Ci -6 alkoxy, haloCi- ⁇ alkyl, haloCi-galkoxy, hydroxyCi- ⁇ alkyl, hydroxyCi -6 alkoxy, Ci -6 alkoxyCi -6 alkyl, Ci -6 alkoxyCi- 6 alkoxy, amino, Ci-ealkylamino, bis(Ci -6 alkyl)amino, aminoCi- ⁇ alkyl, (Ci -6 alkyl)aminoCi.
  • R 11 , R 12 and R 17 are independently hydrogen or a group selected from Ci -b alkyl, carbocyclyl, carbocyclylCi.
  • R 13 , R 14 , R 15 , R 16 and R 18 are independently hydrogen or a group selected from Ci.
  • 1 Y and Y 2 are independently N or CR 8 provided that one of 1 Y and Y 2 is N and the other is
  • R 1 is a ' group selected from Ci -6 alkyl, C2- 6 alkenyl, Ca- ⁇ alkynyl, carbocyclyl, carbocyclylCi.
  • NR 9 CONR 10 R 15 , -NR 9 COCONR 10 R 15 and -NR 9 SO 2 R 10 ; or X-R 1 is -CR 6 R 7 OH;
  • R 2 is a group selected from Ci -6 alkyl, carbocyclyl and heterocyclyl which group is substituted by -NR 17 SO 2 R 18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , -SR 11 , -SOR 11 , -SO 2 R 1 1 ,
  • each R 3 when present, is independently selected from halo, cyano, nitro, -R 13 , -OR 13 , -SR 13 , -SOR 13 , -SO 2 R 13 , -COR 13 , -CO 2 R 13 , -CONR 13 R 14 , -NR 13 R 14 , -NR 13 COR 14 , -NR 13 CO 2 R 14 and -NR 13 SO 2 R 14 ;
  • R and R 5 are independently hydrogen or Ci -6 alkyl; or R 1 and R 4 together with the atom or atoms to which they are attached form a 5- to 10- membered carbocyclic or heterocyclic ring wherein 1 , 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which
  • R 9 and R 10 are independently hydrogen or a group selected from Ci ⁇ alkyl, carbocyclyl, carbocyclylCi-ealkyl, heterocyclyl and which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-ealkyl, Ci-ealkoxy, haloCi_ 6 alkyl, haloCi -6 alkoxy, hydroxyC 1-6 alkyl, hydroxyCi -6 alkoxy, Ci- 6 alkoxyCi -6 alkyl, d- 6 alkoxyCi.
  • Ci- 6 alkylamino bis(Ci -6 alkyl)amino, aminoCi- ⁇ alkyl, (Ci-ealky ⁇ aminoCi-ealkyl, bis(Ci -6 alkyl)aminoC 1-6 alkyl, cyanoCi -6 alkyl, Ci -O alkylsulfonyl, Ci-ealkylsulfonylamino, Ci -6 alkylsulfonyl(Ci.
  • R 11 , R 12 and R 17 are independently hydrogen or a group selected from Ci -6 alkyl, carbocyclyl, carbocyclylCi -6 alkyl, heterocyclyl and heteiOcyclylCi -6 alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C ] -6 alkyl, Ci -6 alkoxy, haloCi_ 6 alkyl, haloCi -6 alkoxy, hydroxyCi -6 alkyl
  • R 13 , R 14 , R 15 , R 16 and R 18 are independently hydrogen or a group selected from Ci. 6 alkyl, carbocyclyl, carbocyclylCi -6 alkyl, heterocyclyl and heterocyclylCi-oalkyl which group is 5 optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci- ⁇ alkyl, Ci -5 alkoxy, haloCi -6 alkoxy, hydroxyCi -6 alkyl, hydroxyCi- ⁇ alkoxy, Ci- ⁇ alkoxyCi-oalkyl, Ci -6 alkoxyCi.6alkoxy, amino, Ci -6 alkylamino, bis(Ci- 6 alkyl)amino, aminoCi. 0 alkyl, bis(Ci -6 alkyl)aniinoCi.
  • formula (I) or a pharmaceutically acceptable salt thereof wherein m is O, 1, 2, 3 or 4; 1Y and Y 2 are independently N or CR 8 provided that one of 1 Y and Y 2 is N and the other is
  • R 1 is a group selected from hydrogen, Ci. 6 alkyl, C 2 - 6 alkenyl, C 2-6 alkynyl, carbocyclyl, carbocyclylCi -6 alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, -R 9 , -OR 9 , -SR 9 , -SOR 9 , -SO 2 R 9 , -COR 9 , -CO 2 R 9 , -CONR 9 R 10 , -NR 9 R 10 , -NR 9 COR 10 , -NR 9 CO 2 R 10 , -NR 9 CONR 10 R 15 , -NR 9 COCONR 10 R 15 and -NR 9 SO 2 R 10 ; R 2 is a group selected from C ⁇ alkyl, carbocyclyl and heterocyclyl which group is substituted by -NR 17 SO 2 R 18
  • R 4 and R 3 are independently hydrogen or or R 1 and R 4 together with the atom or atoms to which they are attached form a 5- to 10- membered carbocyclic or heterocyclic ring wherein 1 , 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, Ci -6 alkoxy, haloCi- 6 alkyl, haloCi -6 alkoxy, hydroxyCi -6 alkyl, hydroxyCi -6 alkoxy, Ci -6 alkoxyCi -6 alkyl, C 1 .
  • Ci -6 alkylamino bis(Ci -6 alkyl)amino, aminoCi_ 6 alkyl, (C 1- ⁇ alkyDaminoCi-ealkyl, bis(Ci. 6 alkyl)aminoCi- 6 alkyl, cyanoCi- ⁇ alkyl, Ci_ 6 alkylsulfonyl, C 1- ⁇ alkylsulfonylamino, Ci -6 alkylsulfonyl(Ci. 6 alkyl)amino, sulfamoyl, Ci -6 alkylsulfamoyl, bis(Ci. 6 alkyl)sulfamoyl, Ci -6 alkanoylamino, carbamoyl, C 1- ⁇ alkylcarbamoyl and bis(Ci -6 alkyl)carbamoyl;
  • R 6 and R 7 are independently selected from hydrogen, halo, cyano, nitro and Ci ⁇ alkyl;
  • R 8 is selected from hydrogen, halo, cyano and Ci ⁇ alkyl;
  • R 9 and R 10 are independently hydrogen or a group selected from Ci -6 alkyl, carbocyclyl, carbocyclylC 1-6 alkyl, heterocyclyl and heterocyclylCi ⁇ alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci- ⁇ alkyl, Ci -6 alkoxy, haloCi_ 6 alkyl, haloCi -0 alkoxy, hydroxyCi- ⁇ alkyl, hydroxyCi -6 alkoxy, Ci- ⁇ alkoxyCi -6 alkyl, amino, Ci.
  • alkylamino bis(C ⁇ - 6 alkyl)amino, aminoCi. 6 alkyl, (Ci -6 alkyl)aminoCi -6 alkyl, bis(Ci. 6 alkyl)aminoCi- 6 alkyl, cyanoCi -6 alkyl, Ci-ealkylsulfonyl, Ci -6 alkylsulfonylamino, C
  • R 11 , R 12 and R 17 are independently hydrogen or a group selected from Ci-ealkyl, carbocyclyl, carbocyclylCi- 6 alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci -6 alkyl, Ci -6 alkoxy, haloCi- ⁇ alkyl, haloCi -6 alkoxy, hydroxyCi -6 alkyl, hydroxyCi-ealkoxy, Ci- 6 alkoxyCi -6 alkyl, amino, Ci -6 alkylamino, bis(Ci.
  • R 13 , R 14 , R 15 , R 16 and R 18 are independently hydrogen or a group selected from C].
  • ealkyl cyanoCi -6 alkyl, Cj- ⁇ alkylsulfonyl, Ci -6 alkylsulfonylamino, Ci. 6 alkylsulfonyl(Ci. ealkyl)amino, sulfamoyl, Ci -6 alkylsulfamoyl, bis(Ci -6 alkyl)sulfamoyl, Ci-ealkanoylamino, C
  • 1 Y and Y 2 are independently N or CR 8 provided that one of 1 Y and Y 2 is N and the other is CR 8 ;
  • R 1 is a group selected from d-ealkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, carbocyclylCi. 6alkyl, heterocyclyl and heterocyclylCi-oalkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, -R 9 , -OR 9 , -SR 9 , -SOR 9 , -SO 2 R 9 , -COR 9 , -CO 2 R 9 , -CONR 9 R 10 , -NR 9 R 10 , -NR 9 COR 10 , -NR 9 CO 2 R 10 , o -NR 9 CONR 10 R 15 , -NR 9 COCONR 10 R 15 and -NR 9 SO 2 R 10 ; or X-R 1 is -CR 6 R 7 OH;
  • R 2 is a group selected from Ci ⁇ alkyl, carbocyclyl and heterocyclyl which group is substituted by -NR 17 SO 2 R 18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , - SR 11 , -SOR 11 , -SO 2 R 11 ,s -COR 11 , -CO 2 R 11 , -CONR 11 R 12 , -NR 11 R 12 , -NR 11 COR 12 , and -NR 11 COCONR 12 R 16 ; each R 3 , when present, is independently selected from halo, cyano, nitro, -R 13 , -OR 13 , -SR 13 , -SOR 13 , -SO 2 R 13 , -COR 13 , -CO 2 R 13 , -CONR 13 R 14 , -NR 13 R 14 , -NR 13 COR 14 , -NR 13
  • Ci- 6 alkylamino bis(Ci -6 alkyl)amino, aminoCi -6 alkyl, (Ci- 6 alkyl)aminoCi- ⁇ alkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, cyanoCi ⁇ alkyl, Ci -6 alkylsulfonyl, Ci- 6 alkylsulfonylamino, Ci.
  • 0 R 6 and R 7 are independently selected from hydrogen, halo, cyano, nitro and Ci -6 alkyl;
  • R 8 is selected from hydrogen, halo, cyano and Ci- ⁇ alkyl;
  • R 9 and R 10 are independently hydrogen or a group selected from Ci -6 alkyl, carbocyclyl, carbocyclylCi -0 alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is optionally substitute
  • Ci -6 alkyl haloCi-ealkoxy, hydroxyCi. 0 alkyl, Ci -0 alkoxyC 1-e alkyl, Ci -6 alkoxyCi. 6 alkoxy, amino, Ci -6 alkylamino, bis(Ci -6 alkyl)amino, aminoCi -6 alkyl, (Ci - ⁇ alkyl)aminoC ⁇ -6 alkyl, bis(Ci. 6 alkyl)aminoCi- 6 alkyl, Ci -6 alkylsulfonyl, Ci.
  • R 11 , R 12 and R 17 are independently hydrogen or a group selected from Ci ⁇ alkyl, carbocyclyl, carbocyclylCi -6 alkyl, heterocyclyl and which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-O alkyl, Ci -O alkoxy, haloCi -6 alkyl, haloCi -6 alkoxy, hydroxyCi ⁇ alkyl, hydroxyCi_ 6 alkoxy, Ci -6 alkoxyCi -6 alkyl, Ci -6 alkoxyCi -6 alkoxy, amino, Ci ⁇ alkylamino, bis(Ci -6 alkyl)amino, aminoCi -6 alkyl, (Ci -b alkyl)amino
  • R 13 , R 14 , R 15 , R lb and R 18 are independently hydrogen or a group selected from Ci -t ,alkyl, carbocyclyl, carbocyclylCi -t ,alkyl, heterocyclyl and heteiOcyclylCi_ b alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-ealkyl, Ci -6 alkoxy, haloCi -b alkyl, haloC ⁇ -6 alkoxy, hydroxyCi -6 alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkyl, Ci -6 alkoxyCi_ 6 alkoxy, amino, Ci- 6 alkylamino, bis(Ci.
  • formula (I) or a pharmaceutically acceptable salt wherein m is O, 1, 2, 3 or 4; 1Y and Y 2 are independently N or CR 8 provided that one of Y and Y 2 is N and the other is CR 8 ;
  • R 1 is a group selected from Ci -6 alkyl, C 2 . 6 alkenyl, C 2-b alkynyl, carbocyclyl, carbocyclylCi. b alkyl, heterocyclyl and heterocyclylCi-oalkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, -R 9 , -OR 9 , -SR 9 , -SOR 9 , -SO 2 R 9 , -COR 9 , -CO 2 R 9 , -CONR 9 R 10 , -NR 9 R 10 , -NR 9 COR 10 , -NR 9 CO 2 R 10 , -NR 9 CONR 10 R 15 , -NR 0 COCONR 10 R 15 and -NR 9 SO 2 R 10 ; or X-R 1 is -CR 6 R 7 OH
  • R 2 is a group selected from Ci- ⁇ alkyl, carbocyclyl and heterocyclyl which group is substituted by -NR 17 SO 2 R 18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , - SR 1 1 , -SOR 11 , -SO 2 R 11 , -COR 11 , -CO 2 R 1 1 , -CONR 11 R 12 , -NR 11 R 12 , -NR 11 COR 12 , and -NR 1 1 COCONR 12 R 16 ; each R 3 , when present, is independently selected from halo, cyano, nitro, -R 13 , -OR 13 , -SR 13 , -SOR 13 , -SO 2 R 13 , -COR 13 , -CO 2 R 13 , -CONR 13 R 14 , -NR 13 R 14 , -NR 13 COR 14 ,
  • R 6 and R 7 are independently selected from hydrogen, halo, cyano, nitro and C[. 6 alkyl;
  • R 8 is selected from hydrogen, halo, cyano and Ci ⁇ alkyl;
  • R 9 and R 10 are independently hydrogen or a group selected from C[.
  • R 11 , R 12 and R 17 are independently hydrogen or a group selected from Ci -6 alkyl, carbocyclyl, carbocyclylC 1-6 alkyl, heterocyclyl and heterocyclylCi-ealkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci -6 alkyl, Ci -6 alkoxy, haloCi- ⁇ alkoxy, hydroxyCi -6 alkyl, hydroxyCu ⁇ alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkyl, Ci -6 alkoxyCi- 6 alkoxy, amino, Ci -6 alkylamino, bis(C 1-6 alkyl)amino, aminoCi- 6 alkyl, (Ci-6alkyl)aminoC ⁇ -6 alkoxy, amino, Ci -6 alkylamino, bis(C 1-6 alkyl)amino, aminoCi- 6 alkyl, (Ci-6alkyl)
  • R 13 , R 14 , R 15 , R 16 and R 18 are independently hydrogen or a group selected from Ci.
  • Ci- 6 alkanoylamino Ci- 6 alkanoyl(Ci_ 6 alkyl)amino, carbamoyl, Ci_ 6 alkylcarbamoyl and bis(Ci -6 alkyl)carbamoyl in the manufacture of a medicament for use in the treatment of proliferative disease.
  • 1 Y and Y 2 are independently N or CR 8 provided that one of 1 Y and Y 2 is N and the other is
  • R 1 is a group selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, carbocyclylQ. ⁇ alkyl, heterocyclyl and which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, -R' , -OR' ,
  • R 2 is a group selected from Ci -6 alkyl, carbocyclyl and heterocyclyl which group is substituted by -NR 17 SO 2 R 18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 1 1 , -SR 1 1 , -SOR 1 1 , -SO 2 R 11 ,
  • each R 3 when present, is independently selected from halo, cyano, nitro, -R 13 , -OR 13 , -R 13 , -SOR 13 , -SO 2 R 13 , -COR 13 , -CO 2 R 13 , -CONR 13 R 14 , -NR 13 R 14 , -NR 13 COR 14 , - NR 13 CO2R 14 and -NR 13 SO 2 R 14 ;
  • R 4 and R 5 are independently hydrogen or Ci.
  • R 1 and R 4 together with the atom or atoms to which they are attached form a 5- to 10- membered carbocyclic or heterocyclic ring wherein 1 , 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-ealkyl, Ci -6 alkoxy, haloCi.
  • R 6 and R 7 are independently selected from hydrogen, halo, cyano, nitro and C ⁇ aHcyl;
  • R 8 is selected from hydrogen, halo, cyano and Ci -6 alkyl;
  • R 9 and R 10 are independently hydrogen or a group selected from carbocyclyl, carbocyclylCi -6 alkyl, heterocyclyl and heteiOcyclylC 1-6 alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-ealkyl, Ci -6 alkoxy, haloCi -6 alkyl, haloCi -6 alkoxy, hydroxyCi_ 6 alkyl, hydroxyCi- ⁇ alkoxy, Ci- 6 alkoxyCi_ 6 alkyl, 0 !
  • Ci-ealkylamino bis(Ci -6 alkyl)amino, aminoCi -6 alkyl, (Ci. 6 alkyl)aminoCi -6 alkyl, bis(C]. 6 alkyl)aminoCi -6 alkyl, Ci- ⁇ alkylsulfonyl, Ci -6 alkylsulfonylamino, Ci.
  • 6 alkylcarbamoyl and bis(Ci -6 alkyl)carbamoyl; R 11 , R 12 and R 17 are independently hydrogen or a group selected from Ci -6 alkyl, carbocyclyl, carbocyclylCi.
  • Ci -6 alkyl haloCi -6 alkoxy, hydroxyCu 6 alkyl, hydroxyCi -b alkoxy, Ci -6 alkoxyCi -6 alkyl, Ci -6 alkoxyCi -6 alkoxy, amino, Ci -6 alkylamino, bis(Ci- 6 alkyl)amino, aminoCi -6 alkyl, (Ci-ealkyDaminoCi- ⁇ alkyl, bis(Ci -6 alkyl)aminoCi_ 6 alkyl, cyanoCi -6 alkyl, Ci-6alkylsulfonyl, Ci-ealkanoylamino, Ci -6 alkanoyl(Ci.
  • R 13 , R 14 , R 15 , R 16 and R 18 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl, carbocyclylCi- ⁇ alkyl, heterocyclyl and heterocyclylCi -6 alkyl which group is 5 optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci- ⁇ alkyl, Ci -6 alkoxy, haloCi -6 alkyl, haloCi.
  • Ci_ 6 alkoxyCi -6 alkyl Ci- ⁇ alkoxyCi- ⁇ alkoxy, amino, Ci- ⁇ alkylamino, bis(C 1 . 6 alkyl)amino, aminoCi -6 alkyl, (Ci. 6 alkyl)aminoCi- 6 alkyl, bis(Ci. 6 alkyl)aminoCi.
  • formula (I) or a pharmaceutically acceptable salt thereof wherein m is O, 1, 2, 3 or 4; 1Y and Y 2 are independently N or CR 8 provided that one of 1 Y and Y 2 is N and the other is
  • R 1 is a group selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, carbocyclylCi. ⁇ alkyl, heterocyclyl and heterocyclylCi- b alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, -R 9 , -OR 9 , -SR 9 , -SOR 9 ,
  • R 2 is a group selected from C ⁇ aHcyl, carbocyclyl and heterocyclyl which group is substituted by -NR 17 SO 2 R 18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , -SR 11 , -SOR 11 , -SO 2 R 1 1 ,
  • each R 3 when present, is independently selected from halo, cyano, nitro, -R 13 , -OR 13 , -R 13 , " SOR 13 , -SO 2 R 13 , -COR 13 , -CO 2 R 13 , -CONR 13 R 14 , -NR 13 R 14 , -NR 13 COR 14 , -
  • R 4 and R 5 are independently hydrogen or Ci. ⁇ alkyi; or R 1 and R 4 together with the atom or atoms to which they are attached form a 5- to 10- membered carbocyclic or heterocyclic ring wherein 1 , 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-ealkyl, Ci-ealkoxy, haloCi.
  • Ci- 6 alkanoylamino Ci- 6 alkanoyl(Ci -6 alkyl)amino, carbamoyl, Ci- ⁇ alkylcarbamoyl and bis(Ci_ 6 alkyl)carbamoyl;
  • R 6 and R 7 are independently selected from hydrogen, halo, cyano, nitro and Ci -6 alkyl;
  • R 8 is selected from hydrogen, halo, cyano and Ci -6 alkyl;
  • R 9 and R 10 are independently hydrogen or a group selected from Ci -6 alkyl, carbocyclyl, carbocyclylC].
  • 6 alkyl, heterocyclyl and heterocyclic i -6 alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy,
  • R 11 , R 12 and R 17 are independently hydrogen or a group selected from C h alky., carbocyclyl, carbocyclylCi.
  • R 13 , R 14 , R 15 , R 16 and R 18 are independently hydrogen or a group selected from carbocyclyl, which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci -6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, hydroxyCi-ealkyl, hydroxyCi -6 alkoxy, Ci -6 alkoxyCi -( ,alkoxy, amino, Ci -6 alkylamino, bis(Ci -6 alkyl)amino, aminoCi -6 alkyl, (Ci- 6 alkyl)aminoCi- ⁇ alkyl, bis(Ci -6 alkyl)aminoCi.
  • formula (I) or a pharmaceutically acceptable salt thereof wherein m is 0, 1, 2, 3 or 4; 1 Y and Y 2 are independently N or CR 8 provided that one of 1 Y and Y 2 is N and the other is
  • R 1 is a group selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, carbocyclylC]. 6alkyl, heterocyclyl and heterocyclylCi- 6 alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, -R 9 , -OR 9 , -SR 9 , -SOR 9 ,o -O 2 R 9 , -COR 9 , -CO 2 R 9 , -CONR 9 R 10 , -NR 9 R 10 , -NR 9 COR 10 , -NR 9 CO 2 R 10 , - NR 9 CONR 10 R 15 , -NR 9 COCONR 10 R 15 and NR 9 SO 2 R 10 ; or X-R 1 is -CR 6 R 7 OH;
  • R 2 is a group selected from Ci -6 alkyl, carbocyclyl and heterocyclyl which group is substituted by -NR 17 SO 2 R 18 and optionally substituted by one or more substituent groups independently selected from halo, cyano, nitro, -R 11 , -OR 11 , -SR 11 , -SOR 11 , -SO 2 R 11 , -COR 11 , -CO 2 R 11 , -CONR 11 R 12 , -NR 11 R 12 , -NR 11 COR 12 , and -NR 11 COCONR 12 R 16 ; each R 3 , when present, is independently selected from halo, cyano, nitro, -R 13 , -OR 13 , -R 13 , " SOR 13 , -SO 2 R 13 , -COR 13 , -CO 2 R 13 , -CONR 13 R 14 , -NR 13 R 14 , -NR 13 COR 14 , - NR 13 CO
  • R 6 and R 7 are independently selected from hydrogen, halo, cyano, nitro and Ci -6 alkyl;
  • R 8 is selected from hydrogen, halo, cyano and Ci. 6 alkyl;
  • R 9 and R 10 are independently hydrogen or a group selected from Ci -6 alkyl, carbocyclyl, carbocyclylCi.galkyl, heterocyclyl and heterocyclylCi-galkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci- ⁇ alkyl, Ci-ealkoxy, haloCi -6 alkyl, haloCi.galkoxy, hydroxyCi- ⁇ alkyl, hydroxyCi -6 alkoxy, Ci- ⁇ alkoxyCi-ealkyl, Ci.
  • Ci -6 alkylamino bis(Ci -6 alkyl)amino, aminoCi_ 6 alkyl, (Ci -6 alkyl)aminoCi- 6 alkyl, bis(Ci -6 alkyl)aminoCi. 6 alkyl, cyanoCi- ⁇ alkyl, Ci -6 alkylsulfonyl, C[. 6 alkylsulfonylamino, Ci.
  • R 11 , R 12 and R 17 are independently hydrogen or a group selected from Ci.
  • R 13 , R 14 , R 1S , R 16 and R 18 are independently hydrogen or a group selected from carbocyclyl, carbocyclylCi- ⁇ alkyl, heterocyclyl and heterocyclylCi ⁇ alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci -6 alkyl, C 1-6 alkoxy, haloCi -6 alkyl, haloC 1-6 alkoxy, hydroxy C i ⁇ alkyl, hydroxyCi.
  • Certain compounds of formula (I) are capable of existing in stereoisomer ⁇ forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention. Solvates and mixtures thereof also form an aspect of the present invention.
  • a suitable solvate of a compound of formula (I) is, for example, a hydrate such as a hemi-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate or an alternative quantity thereof.
  • the present invention relates to the compounds of formula (I) as herein defined as well as to salts thereof.
  • Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula (I) and their pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts of the invention may, for example, include acid addition salts of compounds of formula (I) as herein defined which are sufficiently basic to form such salts.
  • acid addition salts include but are not limited to furmarate, methanesulfonate, hydrochloride, hydrobromide, citrate and maleate salts and salts formed with phosphoric and sulfuric acid.
  • salts are base salts and examples include but are not limited to, an alkali metal salt for example sodium or potassium, an alkaline earth metal salt for example calcium or magnesium, or organic amine salt for example triethylamine, ethanolamine, diethanolamine, triethanolamine, morpholine, iV-methylpiperidine, iV-ethylpiperidine, dibenzylamine or amino acids such as lysine.
  • an alkali metal salt for example sodium or potassium
  • an alkaline earth metal salt for example calcium or magnesium
  • organic amine salt for example triethylamine, ethanolamine, diethanolamine, triethanolamine, morpholine, iV-methylpiperidine, iV-ethylpiperidine, dibenzylamine or amino acids such as lysine.
  • the compounds of formula (I) may also be provided as in vivo hydrolysable esters.
  • An in vivo hydrolysable ester of a compound of formula (I) containing carboxy or hydroxy group is, for example a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid or alcohol.
  • esters can be identified by administering, for example, intravenously to a test animal, the compound under test and subsequently examining the test animal's body fluid.
  • Suitable pharmaceutically acceptable esters for carboxy include Ci- 6 alkoxymethyl esters for example methoxymethyl, Ci- ⁇ alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C 3 - 8 cycloalkoxycarbonyloxyCi.
  • alkyl esters for example 1-cyclohexylcarbonyloxy ethyl, l,3-dioxolen-2-onylmethyl esters for example 5-methyl-l,3-dioxolen-2-onylmethyl, and Ci -6 alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl; and may be formed at any carboxy group in the compounds of this invention.
  • Suitable pharmaceutically acceptable esters for hydroxy include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s.
  • inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s.
  • ⁇ -acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxyniethoxy.
  • a selection of in vivo hydrolysable ester forming groups for hydroxy include Ci-[ 0 alkanoyl, for example formyl, acetyl, benzoyl, phenylacetyl, substituted benzoyl and phenylacetyl; Ci-i 0 alkoxycarbonyl (to give alkyl carbonate esters), for example ethoxycarbonyl; di-Ci- 4 alkylcarbamoyl and ⁇ di-C ⁇ alkylaminoethy I)-N-C i- 4 alkylcarbamoyl (to give carbamates); di-C(- 4 alkylaminoacetyl and carboxy acetyl.
  • ring substituents on phenylacetyl and benzoyl include aminomethyl, Ci -4 alkylaminomethyl and di-(Ci- 4 alkyl)aminomethyl, and morpholino or piperazino linked from a ring nitrogen atom via a methylene linking group to the 3- or 4- position of the benzoyl ring.
  • Other interesting in vivo hydrolysable esters include, for example, R A C(O)OCi -6 alkyl-CO-, wherein R ⁇ is for example, benzyloxy-Ci- 4 alkyl, or phenyl.
  • Suitable substituents on a phenyl group in such esters include, for example, 4-Ci- 4 piperazino-Ci- 4 alkyl, piperazino-Ci- 4 alkyl and morpholmo-Ci- 4 alkyl.
  • the compounds of the formula (I) may be also be administered in the form of a prodrug which is broken down in the human or animal body to give a compound of the formula (I).
  • Various forms of prodrugs are known in the art. For examples of such prodrug derivatives, see: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K.
  • C p . q alkyl includes both straight-chain and branched-chain alkyl groups.
  • references to individual alkyl groups such as "propyl” are specific for the straight chain version only (i.e. /?-propyl and isopropyl) and references to individual branched-chain alkyl groups such as "t ⁇ /Y-butyl” are specific for the branched chain version only.
  • Ci -4 alkyl includes Cialkyl (methyl), C 2 alkyl (ethyl), C 3 alkyl (propyl as rc-propyl and isopropyl) and C 4 alkyl (n-butyl, sec-butyl, isobutyl and tert-hutyl).
  • C p-q alkoxy comprises -O-C p . q alkyl groups.
  • C p-q alkanoyl comprises -C(O)alkyl groups.
  • halo includes fluoro, chloro, bromo and iodo.
  • Carbocyclyl includes “aryl”, “C p- q Cycloalkyl” and “C p - q Cycloalkenyl”.
  • aryl is an aromatic monocyclic, bicyclic or tricyclic carbcyclyl ring system.
  • Heterocyclyl includes “heteroaryl", “cycloheteroalkyl” and “cycloheteroalkenyl”.
  • Heteroaryl is an aromatic monocyclic, bicyclic or tricyclic heterocyclyl, particularly having 5 to 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulfur or oxygen where a ring nitrogen or sulfur may be oxidised.
  • carbocyclylC p-q alkyl comprises C p-q alkyl substituted by carbocyclyl
  • heteiOcyclylC p-q alkyl comprises C p
  • bis(C p-q alkyl)amino comprises amino substituted by 2 C p- q alkyl groups which may be the same or different.
  • HaloC p-q alkyl is a C p . q alkyl group that is substituted by 1 or more halo substituents and particuarly 1, 2 or 3 halo substituents.
  • other generic terms containing halo such as haloC p-q alkoxy may contain 1 or more halo substituents and particluarly 1 , 2 or 3 halo substituents.
  • HydroxyC p-q alkyl is a C p-q alkyl group that is substituted by 1 or more hydroxy 1 substituents and particularly by 1 , 2 or 3 hydroxy substituents.
  • other generic terms containing hydroxy such as hydroxy C p-q alkoxy may contain 1 or more and particularly 1, 2 or 3 hydroxy substituents.
  • Cp. q alkoxyC p-q alkyl is a C p-q alkyl group that is substituted by 1 or more C p-q alkoxy substituents and particularly 1 , 2 or 3 C p-q alkoxy substituents.
  • other generic terms containing C p . q alkoxy such as C p-q alkoxyC P - q alkoxy may contain 1 or more C p- q alkoxy substituents and particularly 1 , 2 or 3 C p-q alkoxy substituents.
  • substituents are chosen from “1 or 2", from “1, 2, or 3” or from “1, 2, 3 or 4" groups or substituents it is to be understood that this definition includes all substituents being chosen from one of the specified groups i.e. all substitutents being the same or the substituents being chosen from two or more of the specified groups i.e. the substitutents not being the same.
  • Proliferative disease(s) includes malignant disease(s) such as cancer as well as non-malignant disease(s) such as inflammatory diseases, obstracutive airways diseases, immune diseases or cardiovascular diseases.
  • Suitable values for any R group or any part or substituted for such groups include: for methyl, ethyl, propyl, butyl, 2-methylpropyl and tert-butyl; or Ci -6 alkyl: Cmalkyl, pentyl, 2,2-dimethylpropyl, 3-methylbutyl and hexyl; or C 3 .
  • cycloalkyl cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; or C 3-6 Cy cloalkylC ⁇ - 4 alkyl: cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl; or aryl: phenyl and naphthyl; or arylCi- 4 alkyl: benzyl, phenethyl, naphthylmethyl and naphthylethyl; or carbocylyl: aiyl, cyclohexenyl and C ⁇ cycloalkyl; or halo: fluoro, chloro, bromo and iodo; or Ci.
  • Ci- 6 alkoxy Ci ⁇ alkoxy, pentyloxy, 1-ethylpropoxy and hexyloxy; or Ci-ealkanoyl: acetyl, propanoyl and 2-methylpropanoyl; or heteroaryl: pyridyl, imidazolyl, quinolinyl, cinnolyl, pyrimidinyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, thiazolyl, triazolyl, oxazolyl, isoxazolyl, furanyl, pyridazinyl, pyrazinyl, indolyl, benzofuranyl, dibenzofuranyl and benzothienyl; or heteroarylCi -4 alkyl: pyrrolylmethyl, pyi ⁇ olylethyl, imidazo
  • m is 0, 1 , 2 or 3.
  • m is 0, 1 or 2. In a further aspect m is 0 or 1. In yet another aspect m is 0 so that R is absent. In yet another aspect m is 1 and R 3 is methyl. 1Y and Y 2
  • 1 Y is N and Y 2 is CR 8 .
  • Y is N and Y 2 is CH.
  • 1 Y is CR 8 and Y 2 is N.
  • 1 Y is CH or CF and Y 2 is N.
  • 1 Y is CH and Y 2 is N.
  • X is a linker group selected from -NR 4 CR 6 R 7 -, -OCR 6 R 7 -, -SCR 6 R 7 -, -S(O)CR 6 R 7 -, -S(O) 2 CR 6 R 7 -, -C(O)NR 4 CR 6 R 7 -, -NR 4 C(O)NR 5 CR 6 R 7 -, -S(O) 2 NR 4 CR 6 R 7 -, -NR 4 C(O)-, -C(O)NR 4 -, -S(O) 2 NR 4 - and -NR 4 S(O) 2 -.
  • X is a linker group selected from -NR 4 CR 6 R 7 -, -OCR 6 R 7 -, -SCR 6 R 7 -, -S(O)CR 6 R 7 -, -S(O) 2 CR 6 R 7 -, -C(O)NR 4 CR 6 R 7 -, -NR 4 C(O)NR 5 CR 6 R 7 -, -S(O) 2 NR 4 CR 6 R 7 , -C(O)NR 4 - and -NR 4 C(O)-.
  • X is a linker group selected from -NR 4 CR 6 R 7 -, -OCR 6 R 7 -, -SCR 6 R 7 -, -S(O)CR 6 R 7 -, -S(O) 2 CR 6 R 7 -, -C(O)NR 4 -, and -NR 4 C(O)-.
  • X is a linker group selected from -NR 4 CR 6 R 7 -, -OCR 6 R 7 -, -SCR 0 R 7 -, -S(O)CR 6 R 7 - and -S(O) 2 CR 6 R 7 -.
  • X is a linker group selected from -SCR 6 R 7 -, -S(O)CR 6 R 7 - and -S(O) 2 CR b R 7 -.
  • X is a linker group selected from -NR 4 CH 2 -, -OCH 2 -,
  • X is a linker group selected from -NR 4 CH 2 -, -OCH 2 -, -SCH 2 -, -S(O)CH 2 -, -S(O) 2 CH 2 -, -C(O)NR 4 -, and -NR 4 C(O)-.
  • X is a linker group selected from -NR 4 CH 2 -, -OCH 2 -,
  • X is a linker group selected from -NR 4 CH 2 -, -OCH 2 -, -SCH 2 -, -S(O)CH 2 - and -S(O) 2 CH 2 -.
  • X is a linker group selected from -NHCH 2 -, -N(CH 3 )CH 2 -,
  • X is a linker group selected from -NHCH 2 -, -N(CH 3 )CH 2 -, -OCH 2 -, -SCH 2 -, -S(O)CH 2 -, -S(O) 2 CH 2 -, -C(O)NH-, -C(O)N(CH 3 )-, -NHC(O)- and -N(CH 3 )C(O)-.
  • X is a linker group selected from -NHCH 2 -, -N(CH 3 )CH 2 -, -OCH 2 -, -OCH(CH 3 )-, -OC(CH 3 ) 2 -, -SCH 2 -, -SCH(CH 3 )-, -SC(CH 3 ) 2 -, -S(O)CH 2 -, -S(O)CH(CH 3 )-, -S(O)C(CHs) 2 -, -S(O) 2 CH 2 -, -S(O) 2 CH(CH 3 )- and -S(O) 2 C(CHs) 2 -.
  • X is a linker group selected from -NHCH 2 -, -N(CH 3 )CH 2 -,
  • X is -SCH 2 - or -S(O) 2 CH 2 -.
  • X is -SCH 2 -, -SCH(CH 3 )- or -SC(CH 3 ) 2 -.
  • X is -S(O)CH 2 -, -S(O)CH(CH 3 )- or -S(O)C(CH 3 ) 2 -.
  • X is -S(O) 2 CH 2 -, -S(O) 2 CH(CH 3 )- or -S(O) 2 C(CH 3 ) 2 -.
  • X is -S(O) 2 CH 2 -.
  • X is -S(O) 2 C(CH 3 ) 2 -.
  • R 1 is a group selected from C ⁇ alkyl, C 3- l ocycloalkyl, aryl, C 3 .iocycloalkylCi-- ⁇ alkyl, arylC 1 . 4 a.kyl, cycloheteroalkyl, heteroaryl, cycloheteroalkylCualkyl, heteroarylCi -4 alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R 9 , -OR 9 , -COR 9 , - CONR 9 R 10 , -NR 9 R 10 and -NR 9 COR 10 .
  • R 1 is a group selected from adamantyl, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyriniidinyl, pyrazinyl, pyiTolidinylmethyl, pyrrolidinylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, pyrazolylethyl, furanylmethyl, furanylethyl, thienylmethyl, thienylethyl, pyridinylmethyl, pyridinylethyl,
  • R 1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH 3 , -CONH 2 and -CONHCH 3 .
  • R 1 is a group selected from methyl, isopropyl, cyclopropyl, cyclohexyl, -CH 2 CH 2 OH, -, -CH 2 CH 2 NC(O)CH 3 , phenyl, 4-fluorophenyl, 2-chlorophenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 2-methylphenyl, 4-acetamidophenyl, 4- aminophenyl, , pyi ⁇ din-4-yl, pyridin-2-yl, 2-oxopyrolidin-3-yl,, thiazol-2-yl, 4- methylthiazol-2-yl, and 3-methyl-l,3,4-thiadiazol-2-yl.
  • R 1 is methyl.
  • X-R 1 is -C(CH 3 ) 2 OH or -CH 2 OH.
  • X-R 1 is -CH 2 OH.
  • R is selected from carbocyclyl or heterocyclyl which group is substituted by -NR 17 SO 2 R 18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 1 ', -OR 1 ⁇ -COR 1 ⁇ - CONR 11 R 12 , -NR 11 R 12 and -NR 11 COR 12 .
  • R 2 is selected from carbocyclyl or heterocyclyl which group is substituted by -NHSO 2 R 18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 1 1 , -OR 11 , -COR 11 , - CONR 11 R 12 , -NR 11 R 12 and -NR 11 COR 12 .
  • R" is selected from 5 or 6 membered carbocyclyl or
  • R 2 is selected from 5 or 6 membered carbocyclyl oro heterocyclyl which group is substituted by -NHSO 2 R 18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 1 , -OR 11 , -COR 11 , -CONR 11 R 12 , -NR 11 R 12 and -NR 11 COR 12 .
  • R 2 is selected from a 6 membered aryl and 5 or 6 membered heteroaryl which group is substituted by -NR 17 SO 2 R 18 and optionallys substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , -COR 11 , -CONR 11 R 12 , -NR 11 R 12 and -NR 11 COR 12 .
  • R 2 is selected from a 6 membered aryl and 5 or 6 membered heteroaryl which group is substituted by -NHSO 2 R and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 ,Q -OR 11 , -COR 11 , -CONR 11 R 12 , -NR 11 R 12 and -NR 11 COR 12 .
  • R 2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is substituted by -NR 17 SO 2 R 18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 1 1 , -OR 1 1 , -COR 11 , -CONR 11 R 12 ,5 -NR 11 R 12 and -NR 1 ' COR 12 .
  • R 2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is substituted by -NHSO 2 R 18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , -COR 1 1 , -CONR 11 R 12 , -NR 1 1 R 12 and 0 -NR 1 1 COR 12 .
  • R 2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is substituted by -NR 17 SO 2 R 18 and optionally substituted by one or more substituent group independently selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH 2 , -CONHCH 3 and -CON(CH 3 ) 2 .
  • R 2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is substituted by -NHSO 2 R 18 and optionally substituted by one or more substituent group independently selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH 2 , -CONHCH 3 and -CON(CH 3 ) 2 .
  • R 2 is phenyl or pyridylsubstituted by -NR 17 SO 2 R 18 and optionally substituted by one or more substituent group independently selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH 2 , -CONHCH 3 and -CON(CH 3 ) 2 .
  • R is phenyl or pyridyl substituted by -NHSO 2 R and optionally substituted by one or more substituent group independently selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH 2 , -CONHCH 3 and -CON(CH 3 ) 2 .
  • R 2 is phenyl substituted by -NHSO 2 R 18 and optionally substituted by one or more substituent group independently selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH 2 , -CONHCH 3 and -CON(CH 3 ) 2 .
  • R 2 is phenyl or pyridyl optionally substituted by -NR 17 SO 2 R 18 .
  • R is phenyl or pyridyl optionally substituted by -NHSO 2 R .
  • R 2 is
  • a 1 and A 2 are selected from CH or N provided that at least one of A 1 or A 2 is CH.
  • R 2 is
  • a 1 and A 2 are selected from CH or N provided that at least one of A 1 or
  • a " is CH H..
  • R is hydrogen or methyl. In another aspect R 4 is hydrogen.
  • X is -NR 4 CR 6 R 7 -, -NR 4 C(O)CR 6 R 7 -, -NR 4 C(O)NR 5 CR 6 R 7 -, -NR 4 S(O) 2 CR 6 R 7 -, -NR 4 C(O)-, -NR 4 C(O)NR 5 - Or -NR 4 S(O) 2 -, R 1 and R 4 together with the atom or atoms to which they are attached form a 5- to 10- membered heterocyclic ring wherein 1, 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci- ⁇ alkyl, Q-galkoxy, haloCi -6 alkyl, haloCi- ⁇ alkoxy, hydroxyCi- ⁇ alkyl, hydroxyCi.
  • Ci_ 6 alkylamino bis(Ci- 6 alkyl)amino, aminoC 1-6 alkyl, (Ci -6 alkyl)aminoC t .oalkyl,s bis(Ci. 6 alkyl)aminoCi.
  • R 1 and R 4 together with the atom or atoms to which they are attached form a 5- or 6- membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci ⁇ alkyl, Ci -6 alkoxy, haloCi- ⁇ alkyl, haloCi -6 alkoxy, 5 hydroxyCi_ 6 alkyl, hydroxyCi- ⁇ alkoxy, Ci -6 alkoxyCi
  • R 5 is hydrogen or methyl. In another aspect R 3 is hydrogen. In another aspect R 5 is methyl.
  • R 6 is hydrogen or methyl. In another aspect R is hydrogen.
  • R 6 is methyl
  • R 7 is hydrogen or methyl. In another aspect R 7 is hydrogen, In another aspect R 7 is methyl.
  • R s is hydrogen or halo.
  • R 8 is hydrogen or fluoro.
  • R 8 is hydrogen.
  • R 9 is hydrogen or C M alkyl optionally substituted by 1, 2 or 3 substituent groups selected from halo, cyano, nitro, hydroxy, Ci. 4 alkoxy, amino, Cmalkylamino and bis(Ci- 4 alkyl)amino.
  • R 9 is hydrogen or Ci_ 4 alkyl optionally substituted by 1, 2 or 3 halo substituents.
  • R 9 is hydrogen, methyl or trifluoromethyl.
  • R 10 is hydrogen
  • R 1 ' is hydrogen or a group selected from C1. 4 a.kyl, aiyl and cycloheteroalkyl which group is optionally substituted by 1 , 2 or 3 groups selected from halo, hydroxy and cyano.
  • R 11 is hydrogen, methyl optionally substituted with hydroxy or cyano, phenyl or pyrrolidinyl. In another aspect R 11 is hydrogen or methyl.
  • R 12 is hydrogen or methyl.
  • R 17 is hydrogen or methyl.
  • R 17 is hydrogen or a group selected from C ⁇ alkyl, aiyl and cycloheteroalkyl which group is optionally substituted by 1, 2 or 3 groups selected from halo, hydroxy and cyano.
  • R 17 is hydrogen, methyl optionally substituted with hydroxy or cyano, phenyl or pyrrolidinyl.
  • R 17 is hydrogen or methyl.
  • R is hydrogen
  • R 18 is hydrogen or a group selected from C ⁇ . 6 alkyl
  • R 8 is hydrogen or a group selected from Ci -6 alkyl, cyanoCi-ealkyl, Ci -6 alkylsulfonyl, Ci. ⁇ alkylsulfonylamino, Ci- ⁇ alkylsulfony ⁇ C ! . 6 alkyl)amino, sulfamoyl, Ci ⁇ alkylsulfamoyl, bis(Ci. 6 alkyl)sulfamoyl, Ci -6 alkanoylamino, Ci. 6 alkanoyl(Ci -0 alkyl)amino, carbamoyl, Ci_ 6 alkylcarbamoyl and bis(Ci- 6 alkyl)carbamoyl.
  • R 8 is hydrogen or a group selected from Ci -6 alkyl,
  • R 18 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazoylmethyl, isoxazolyl, pyrazolyl, pyridinyl and pyrimidinyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci -6 alkyl, Ci- ⁇ alkoxy, haloCi- ⁇ alkyl, haloCi.
  • R is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 (cyclopropyl), -CH 2 CH 2 NMe 2 , -CH(CH 3 )CH 2 OH, -C(CH 3 ) 2 CH 2 OH,
  • R is hydrogen or a group selected from methyl, ethyl, propyl, butyl, cyclopropyl, and 4-flurophenyl.
  • 1 Y and Y 2 are independently N or CR 8 provided that one of 1 Y and Y 2 is N and the other is
  • X is a linker group selected from -NR 4 CR 6 R 7 -, -OCR 6 R 7 -, -SCR 6 R 7 -, -S(O)CR 6 R 7 -,
  • R 1 is a group selected from Ci -6 alkyl, carbocyclyl, carbocyclylC
  • X-R 1 is -C(CH 3 ) 2 OH or -CH 2 OH;
  • R 2 is selected from aryl and heteroaryl which group is substituted by -NR 7 SO 2 R 18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , -COR 11 , -CONR 11 R 12 , -NR 11 R 12 and -NR 11 COR 12 ; each R 3 , when present, is methyl; R 4 and R 5 are independently hydrogen or Ci -6 alkyl; or, when X is -NR 4 CR 6 R 7 -, -NR 4 C(O)NR 5 CR 6 R 7 -, -NR 4 C(O)- or -NR 4 S(O) 2 -, R 1 and R 4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo,
  • R 8 is selected from hydrogen, halo, cyano and
  • R 9 and R 10 are independently hydrogen or a group selected from Ci -6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci- ⁇ alkyl, Ci -6 alkoxy, haloCi -6 alkyl, haloCi.
  • R 11 , R 12 and R 17 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci -6 alkyl, C ⁇ alkoxy, haloCi. ealkyl, haloCi- ⁇ alkoxy, hydroxyCi -6 alkyl, hydroxyCi- ⁇ alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkyl, Cj-
  • R 18 is hydrogen or a group selected from Ci -6 alkyl, C 3 .6cycloakyl, aryl, heteroaryl, arylCi. 6 alkyl and heteroarylCi- ⁇ alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci.
  • Ci -6 alkylsulfonyl C 1- 6 alkylsulfonylamino
  • sulfamoyl bis(Ci. 6 alkyl)sulfamoyl
  • Ci- ⁇ alkanoylamino Ci -6 alkanoyl(C ⁇ . 6 alkyl)amino, carbamoyl, Ci- 6 alkylcarbamoyl and bis(Ci -6 alkyl)carbamoyl.
  • 1 Y and Y 2 are independently N or CR 8 provided that one of 1 Y and Y 2 is N and the other is
  • X is a linker group selected from -NR 4 CH 2 -, -OCH 2 -, -OCH(CH 3 )-, -OC(CH 3 ) 2 -, -SCH 2 -,
  • R 1 is a group selected from adamantyl, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, furanylmethyl, furanylethyl, thienylmethyl, thienylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinyl
  • each R 3 when present, is methyl
  • R 4 is hydrogen or Ci -6 alkyl; or, when X is -NR 4 CH 2 - or -NR 4 C(O)-, R 1 and R 4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C ⁇ alkyl, Ci.
  • R 8 is selected from hydrogen, halo, cyano and
  • R 9 and R 10 are independently hydrogen or a group selected from Ci -6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci. 6 alkyl, Ci -6 alkoxy, haloCi -6 alkyl, haloCi. 6alkoxy, hydiOxyCi -6 alkyl, hydroxyCi. 6 alkoxy, Ci -6 alkoxyC 1-6 alkyl, Ci- 6 alkoxyCi.6alkoxy,0 amino, Ci -6 alkylamino and bis(Ci -6 alkyl)amino;
  • R 11 and R 12 are independently hydrogen or a group selected from C 1-6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci -6 alkyl, Ci. 6 alkoxy, haloCi -6 alkyl, haloCi- ⁇ alkoxy, hydiOxyCi -6 alkyl, hydroxyCi. 6 alkoxy, Ci -6 alkoxyCi -6 alkyl, Ci -6 alkoxyC 1-6 alkoxy,S amino, C 1-6 alkylamino and bis(Ci-6alkyl)amino; and
  • R 18 is hydrogen or a group selected from Ci ⁇ alkyl, C 3-6 cycloakyl, aryl, heteroaiyl, arylCi- 6alkyl and heteroarylCi.
  • ⁇ alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-ealkyl, Ci -6 alkoxy, haloCi- 6alkyl, haloCi -6 alkoxy, hydroxyCi ⁇ alkyl, hydroxyCi.ealkoxy, Ci- ⁇ alkoxyCi- ⁇ alkyl, Ci-o 6 alkoxyC
  • X is a linker group selected from -S(O) 2 CH 2 -, -S(O) 2 CH(CH 3 )- and -S(O) 2 C(CH 3 V;
  • R 1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH 3 , -CONH 2 and -CONHCH 3 ; or -XR 1 is -C(CH 3 ) 2 OH or -CH 2 OH; R 2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furany
  • R 3 when present, is methyl;
  • R 11 and R 12 are independently hydrogen or a group selected from carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci -6 alkyl, Ci -6 alkoxy, haloCi -6 alkyl, haloCi.
  • R 18 is hydrogen or a group selected from C 1-6 alkyl, C 3-6 cycloakyl, aryl, heteroaryl, arylCj.
  • X is a linker group selected from -S(O) 2 CH 2 -, -S(O) 2 CH(CH 3 )- and -S(O) 2 C(CH 3 ) 2 -;
  • Y is CH and Y 2 is N.
  • R 1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH 3 , -CONH 2 and -CONHCH 3 ;
  • R 2 is phenyl or pyridyl substituted by -NHSO 2 R 18 and optionally substituted by one or more substituent group independently selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH 2 , -CONHCH 3 and -CON(CH 3 ) 2 ;
  • R 3 is methyl
  • R 18 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t- butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazoylmethyl, isoxazolyl, pyrazolyl, pyridinyl and pyrimidinyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci- 6 alkyl, Ci- ⁇ alkoxy, haloCi -6 alkyl, haloCi -6 alkoxy, hydroxyCi -6 alkyl, hydroxyCi- ⁇ alkoxy, Ci -6 alkoxyCi -6 alkyl, Ci -6 alkoxyCi -6 alkoxy, amino, Ci -6 alkylamino, bis
  • X is a linker group selected from -S(O) 2 CH 2 -, -S(O) 2 CH(CH 3 )- and -S(O) 2 C(CH 3 ) 2 -; 1 Y is CH and Y 2 is N.
  • R 1 is a group selected from methyl, isopropyl, cyclopropyl, cyclohexyl, -CH 2 CH 2 OH, -CH 2 CH 2 NC(O)CH 3 , phenyl, 4-fluorophenyl, 2-chlorophenyl, 2-trifluoromethylphenyl, 2- methoxyphenyl, 2-methylphenyl, 4-acetamidophenyl, 4-aminophenyl, pyridin-4-yl, pyridin-2-yl, 2-oxopyrolidin-3-yl,, thiazol-2-yl, 4-methylthiazol-2-yl, and 3 -methyl- 1,3,4- thiadiazol-2-yl; R 2 is a group selected from methyl, isopropyl, cyclopropyl, cyclohexyl, -CH 2 CH 2 OH, -CH 2 CH 2 NC(O)CH 3 , phenyl, 4-fluorophenyl
  • a 1 and A 2 are selected from CH or N provided that at least one of A 1 or A 2 is CH;
  • R 17 is hydrogen
  • R 18 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH?(cyclopropyl), -CH 2 CH 2 NMe 2 , -CH(CH 3 )CH 2 OH, -C(CH 3 ) 2 CH 2 OH, -CH 2 CH 2 OH,
  • -CH 2 CH 2 CH 2 OH 4-methylphenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4-flurophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, thien-2-yl, -CH 2 (imidazol-2-yl), -CH 2 (imidazol-3-yl), isoxazolyl-3-yl, 6-oxo-lH-piyrdin-2-yl, 5-methylisoxazol-3-yl, l-methylpyrazol-4-yl,
  • 1 Y and Y 2 are independently N or CR 8 provided that one of 1 Y and Y 2 is N and the other is CR 8 ;
  • X is a linker group selected from -NR 4 CR 6 R 7 -, -OCR 6 R 7 -, -SCR 6 R 7 -, -S(O)CR 6 R 7 -,
  • R 1 is a group selected from C ⁇ -6 alkyl, carbocyclyl, carbocyclylCi- ⁇ alkyl, heterocyclyl and heterocyclylCi -6 alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R 9 , -OR 9 , -COR 9 , -CONR 9 R 10 , -NR 9 R 10 and
  • X-R 1 is -C(CH 3 ) 2 OH or -CH 2 OH;
  • R 2 is selected from aryl and heteroaryl which group is substituted by -NR 17 SO 2 R 18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 1 1 , -COR 1 1 , -CONR 11 R 12 , -NR 11 R 12 and -NR 11 COR 12 ;
  • R 3 is methyl
  • R 4 and R 5 are independently hydrogen or or, when X is -NR 4 CR 6 R 7 -, -NR 4 C(O)NR 5 CR 6 R 7 -, -NR 4 C(O)- or -NR 4 S(O) 2 -, R 1 and R 4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci -b alkyl, Ci -6 alkoxy, haloCi -6 alkyl, haloCi -6 alkoxy, hydroxyCi -6 alkyl, hydroxy C i -6 alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkyl, Ci -6 alkoxyCi -b alkoxy, amino, d- ⁇ alkylamino, bis(Ci-
  • R 6 and R 7 are independently selected from hydrogen, halo, cyano, nitro and Ci ⁇ alkyl;
  • R 8 is selected from hydrogen, halo, cyano and R 9 and R 10 are independently hydrogen or a group selected from C 1-6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci. 6 alkyl, Ci -6 alkoxy, haloCi -b alkyl, haloCi. b alkoxy, hydroxyCi- ⁇ alkyl, hydroxyCi ⁇ alkoxy, Ci- 6 alkoxyCi.
  • R 11 , R 12 and R 17 are independently hydrogen or a group selected from C
  • R 18 is hydrogen or a group selected from Ci -6 alkyl, C 3-6 cycloakyl, aryl, heteroaryl, arylCi- 6 alkyl and heteroaiylCi -6 alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci -6 alkyl, C 1-6 alkoxy, haloCi- 6 alkyl, haloCi -6 alkoxy, hydroxyCi- 6 alkyl, hydroxyCi -6 alkoxy, Ci -6 alkoxyCi.
  • Y and Y are independently N or CR provided that one of 1 Y and Y 2 is N and the other is CR 8 ;
  • X is a linker group selected from -NR 4 CH 2 -, -OCH 2 -, -OCH(CH 3 )-, -OC(CH 3 ) 2 -, -SCH 2 -, -SCH(CH 3 )-, -SC(CH 3 ),-, -S(O)CH 2 -, -S(O)CH(CH 3 )-, -S(O)C(CH 3 V, -S(O) 2 CH 2 -, -S(O) 2 CH(CH 3 )-, -S(O) 2 C(CH 3 V, -C(O)NR 4 - and -NR 4 C(O)-;
  • R 1 is a group selected from adamantyl, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl
  • R 2 is selected from 5 or 6 membered aryl and heteroaiyl which group is substituted by -NHSO 2 R 18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , -COR 11 , -CONR 11 R 12 , -NR 11 R 12 and -NR 11 COR 12 ;
  • R 3 is methyl;
  • R 4 is hydrogen or Ci. 6 alkyl; or, when X is -NR 4 CH 2 - or -NR 4 C(O)-, R 1 and R 4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci -6 alkyl, Ci -6 alkoxy, haloCi- 6 alkyl, haloCi -6 alkoxy, hydroxyCi -6 alkyl, hydroxyCi.
  • Ci- 6 alkoxyCi -6 alkoxy amino, Ci- 6 alkylaniino, bis(Ci_ 6 alkyl)amino, aminoCi -6 alkyl, (Ci- 6 alkyl)aminoC 1-6 alkyl, bis(Ci. 6 alkyl)aminoCi. 6 alkyl, cyanoCi -6 alkyl, Ci- ⁇ alkylsulfonylamino, C ⁇ .
  • R 8 is selected from hydrogen, halo, cyano and Ci -6 alkyl;
  • R 9 and R 10 are independently hydrogen or a group selected from Ci ⁇ alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C ⁇ alkyl, Ci -6 alkoxy, halod ⁇ alkyl, haloCi- ⁇ alkoxy, hydroxyCi -5 alkyl, hydroxyCi- 6 alkoxy, Ci-ealkoxyCi- ⁇ alkyl, Ci- ⁇ alkoxyCi- ⁇ alkoxy, amino, Cj- ⁇ alkylamino and bis(C[. 6 alkyl)amino;
  • R 11 and R 12 are independently hydrogen or a group selected from Ci ⁇ alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci -6 alkyl, haloCi -6 alkyl, haloCi. 6 alkoxy, hydroxyCi -b alkoxy, C 1-6 alkoxyCi -6 alkyl, Ci -6 alkoxyCi -6 alkoxy, amino, Ci-galkylamino and bis(Ci. 6 alkyl)amino; and
  • R 18 is hydrogen or a group selected from Ci -6 alkyl, C 3-6 cycloakyl, aryl, heteroaiyl, arylQ. 6 alkyl and heteroarylCi -6 alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci -6 alkyl, C 1-6 alkoxy, haloCi- ealkyl, haloCi -6 alkoxy, hydiOxyCi -6 alkyl, hydroxyCi -6 alkoxy, Ci.
  • Y is CH and Y 2 is N;
  • X is a linker group selected from -S(O) 2 CH 2 -, -S(O) 2 CH(CH 3 )- and -S(O) 2 C(CH 3 ) 2 -;
  • R 1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH 3 , -CONH 2 and -CONHCH 3 ; or -XR 1 is -C(CH 3 ) 2 OH or -CH 2 OH;
  • R 2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl and thiazolyl which group is substituted by -NHSO 2 R 18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , -COR 11 , -CONR 11 R 12 , -NR 11 R 12 and -NR 11 COR 12 ;
  • R 3 is methyl
  • R 11 and R 12 are independently hydrogen or a group selected from Ci -6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci -6 alkyl, Ci -6 alkoxy, haloCi- 6 alkyl, haloCj.
  • R 18 is hydrogen or a group selected from Ci -6 alkyl, C 3-6 cycloakyl, aryl, heteroaryl, arylCi. b alkyl and heteroarylCi -6 alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci ⁇ alkyl, Ci -6 alkoxy, haloCi- ealkyl, hydroxyC 1-6 alkyl, hydroxyCi. 6 alkoxy, Ci -6 alkoxyCi -6 alkyl, Ci-
  • Ci 6 alkoxyC
  • Ci_ 6 alkanoylamino Ci_ 6 alkanoyl(Ci-6alkyl)amino, carbamoyl, Ci- 6 alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.
  • X is a linker group selected from -S(O) 2 CH 2 -, -S(O) 2 CH(CH 3 )- and -S(O) 2 C(CHs) 2 -; 1 Y is CH and Y 2 is N.
  • R 1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, pyridinyl, pyrazolylethyl, furanylniethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH 3 , -CONH 2 and -CONHCH 3 ;
  • R is phenyl or pyridyl substituted by -NHSO 2 R and optionally substituted by one or more substituent group independently selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH 2 , -CONHCH 3 and -CON(CH 3 ) 2 ; R 3 is methyl; and
  • R 18 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t- butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazoylmethyl, isoxazolyl, pyrazolyl, pyridinyl and pyrimidinyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci -6 alkyl, Ci. 6 alkoxy, haloCi -6 alkyl, haloCi.
  • m is 1 ;
  • X is a linker group selected from -S(O) 2 CH 2 -, -S(O) 2 CH(CH 3 )- and -S(O) 2 C(CH 3 ) 2 -;
  • Y is CH and Y 2 is N.
  • R 1 is a group selected from methyl, isopropyl, cyclopropyl, cyclohexyl, -CH 2 CH 2 OH,
  • a 1 and A 2 are selected from CH or N provided that at least one of A 1 or A 2 is CH;
  • R 17 is hydrogen
  • R 18 is hydrogen or a group selected from methyl, ethyl, propyl, i- propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 (cyclopropyl), -CH 2 CH 2 NMe 2 , -CH(CH 3 )CH 2 OH, -C(CHs) 2 CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, 4-methylphenyl, 4-chlorophenyl, 4-trifluoroniethylphenyl, 4-flurophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, thien-2-yl, -CH 2 (imidazol-2-yl), -CH 2 (imidazol-3-yl), isoxazolyl-3-yl, 6-o
  • Another aspect of the invention provides a compound, or a combination of compounds, selected from any one of the Examples or a pharmaceutically acceptable salt thereof.
  • the invention also provides processes for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a suitable base such as triethylamine
  • solvent such as tetrahydrofuran or N, iV-dimethylformamide.
  • a suitable reducing agent such as NaCNBH 3
  • a suitable base such as sodium hydroxide and a solvent such as ⁇ iV-dimethylformamide.
  • a suitable base such as sodium hydride or potassium t ⁇ /'f-butoxide
  • a suitable solvent such as tetrahydrofuran or N, JV-dimethylformamide.
  • suitable organometallic reagents of fomula (XI) and formula (XII) such as the grignard reagent in a suitable solvent.
  • R 6 and R 7 are different then it may be possible to use techniques known in the literature such the conversion of a compound of formula (X) to the Weinreb amide and reaction with an organometallic reagent of formula (XI) and then reaction with an organometallic reagent of formula (XII) in a subsequent step.
  • a compound of formula (I) may be prepared from a compound of formula (XIII), wherein L 2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O) 2 Me etc.), with a suitable organometallic reagent (such as the boronic acid R 2 B(OH) 2 or the boronic ester R 2 B(OR) 2 etc.) in the presence of a suitable metal catalyst (such as palladium or copper) in a suitable solvent such as 1,4-dioxane.
  • L 2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O) 2 Me etc.)
  • a suitable organometallic reagent such as the boronic acid R 2 B(OH) 2 or the boronic ester R 2 B(OR) 2 etc.
  • a suitable metal catalyst such as palladium or copper
  • a compound of formula (I) may be prepared from a compound of formula (XIII), wherein L 2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O) 2 Me etc.), by reaction with the required amine, alcohol or thiol in the presence of a suitable base such as potassium carbonate in a suitable solvent such as
  • a compound of formula (XIII) may be transformed into another compound of formula (XIII) by techniques such as oxidation, alkylation, reductive amination etc., either listed above or otherwise known in the literature.
  • a suitable base such as triethylamine
  • a solvent such as tetrahydrofuran or N, N-dimethylformamide.
  • a suitable base such as sodium hydroxide
  • solvent such as iV,iV-dimethylformamide
  • a suitable base such as sodium hydride or potassium t ⁇ vt-butoxido
  • a suitable solvent such as tetrahydrofuran or N, JV-dimethylformamide.
  • a compound of formula (XVII) may be prepared by the reaction of a compound of formula (XVII), with suitable organometallic reagents of fomula (XI) and formula (XII) such as the gi ⁇ gnard reagent in a suitable solvent.
  • suitable organometallic reagents of fomula (XI) and formula (XII) such as the gi ⁇ gnard reagent in a suitable solvent.
  • R 6 and R 7 are different then it may be possible to use techniques known in the literature such the conversion of a compound of formula (XVII) to the Weinreb amide and reaction with an organometallic reagent of formula (XI) and then reaction with an organometallic reagent of formula (XII) in a subsequent step .
  • a compound of formula (IV) may be prepared from a compound of formula (XIV), wherein L 2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O) 2 Me etc.) and L 1 is a leaving group (such as halo, tosyl, mesyl etc.), with a suitable organometallic reagent (such as the boronic acid R ⁇ B(OH) 2 or the boronic ester R-B(OR) 2 etc.) in the presence of a suitable metal catalyst (such as palladium or copper) in a suitable solvent such as 1 ,4- dioxane.
  • a suitable organometallic reagent such as the boronic acid R ⁇ B(OH) 2 or the boronic ester R-B(OR) 2 etc.
  • a suitable metal catalyst such as palladium or copper
  • a compound of formula (IV) may be prepared from a compound of formula (XIV), wherein L is a leaving group (such as halo, tosyl, mesyl, -SMe, - S(O) 2 Me etc.), by reaction with the required amine, alcohol or thiol in the presence of a suitable base such as potassium carbonate in a suitable solvent such as N, N- dimethy If ormamide .
  • L is a leaving group (such as halo, tosyl, mesyl, -SMe, - S(O) 2 Me etc.)
  • a compound of formula (X) may be prepared from a compound of formula (XVII), wherein L 2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O) 2 Me etc.) and R is a hydrogen or C ⁇ alkyl group, with a suitable organometallic reagent (such as the boronic acid R"B(OH) 2 or the boronic ester R B(OR) 2 etc.) in the presence of a suitable metal catalyst (such as palladium or copper) in a suitable solvent such as 1,4-dioxane.
  • a suitable organometallic reagent such as the boronic acid R"B(OH) 2 or the boronic ester R B(OR) 2 etc.
  • a suitable metal catalyst such as palladium or copper
  • a compound of formula (X) may be prepared from a compound of formula (XVII), wherein L 2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O) 2 Me etc.), by reaction with the required amine, alcohol or thiol in the presence of a suitable base such as potassium carbonate in a suitable solvent such as iV.iV-dimethylformamide.
  • a suitable base such as potassium carbonate
  • a suitable solvent such as iV.iV-dimethylformamide.
  • a compound of formula (XVIII) may be prepared from a compound of formula
  • L 2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O) 2 Me etc.), with a suitable organometallic reagent (such as the boronic acid R 2 B(OH) 2 or the boronic ester R 2 B(OR) 2 etc.) in the presence of a suitable metal catalyst (such as palladium or copper) in a suitable solvent such as 1,4-dioxane.
  • a suitable organometallic reagent such as the boronic acid R 2 B(OH) 2 or the boronic ester R 2 B(OR) 2 etc.
  • a suitable metal catalyst such as palladium or copper
  • a compound of formula (XVIII) may be prepared from a compound of formula (XIX), wherein L 2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O) 2 Me etc.), by reaction with the required amine, alcohol or thiol in the presence of a suitable base such as potassium carbonate in a suitable solvent such as N, iV-dimethylformamide.
  • a suitable base such as potassium carbonate
  • a suitable solvent such as N, iV-dimethylformamide
  • a compound of formula (XX) may be prepared from a compound of formula (XXI), wherein L 2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O) 2 Me etc.), with a suitable organometallic reagent (such as the boronic acid R 2 B(OH) 2 or the boronic ester R 2 B(OR) 2 etc.) in the presence of a suitable metal catalyst (such as palladium or0 copper) in a suitable solvent such as 1,4-dioxane.
  • L 2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O) 2 Me etc.)
  • a suitable organometallic reagent such as the boronic acid R 2 B(OH) 2 or the boronic ester R 2 B(OR) 2 etc.
  • a suitable metal catalyst such as palladium or0 copper
  • a compound of formula (XX) may be prepared from a compound of formula (XXI), wherein L 2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O) 2 Me etc.), by reaction with the required amine, alcohol or thiol in the presence of a suitable base such as potassium carbonate in a suitable solvents such as iV,iV-dimethylformamide.
  • a compound of formula (I), wherein L 1 is a leaving group (such as halo, tosyl, mesyl etc.), may be prepared by the reaction of a compound of formula (XXII) with a compound of formula (XXIII) optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as N, Af-dimethylformamide.
  • a compound of formula (XXII) may be transformed into another compound of formula (XXII) by techniques such as oxidation, alkylation, reductive animation etc., either listed above or otherwise known in the literature.
  • a compound of formula (IV), wherein L 1 is a leaving group (such as halo, tosyl, mesyl etc.) may be prepared by the reaction of a compound of formula (XXIV) with a compound of formula (XXIII) optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as N, N-dimethylforrnamide.
  • a compound of formula (X), wherein L is a leaving group (such as halo, tosyl, mesyl etc.) and R is a hydrogen or a Ci -4 alkyl group, may be prepared by the reaction of a compound of formula (XXV) with a compound of formula (XXIII) optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as N,N- dimethy lformamide .
  • a suitable base such as triethylamine
  • a suitable solvent such as N,N- dimethy lformamide
  • a compound of formula (XVIII), wherein L 1 is a leaving group (such as halo, tosyl, mesyl etc.), may be prepared by the reaction of a compound of formula (XXVI) with a compound of formula (XXIII) optionally in the presence of a suitable base such as s triethylamine in a suitable solvent such as iV,N-dimethylformamide.
  • a compound of formula (XX), wherein L 1 is a leaving group (such as halo, tosyl, mesyl etc.) and L 2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O) 2 Me etc.), may be prepared by the reaction of a compound of formula (XXVII) with a compound ofo formula (XXIII) optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as N, N-dimethylformaniide.
  • a compound of formula (XIII), wherein L 1 is a leaving group (such as halo, tosyl, mesyl etc.) and L 2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O) 2 Me etc.),s may be prepared by the reaction of a compound of formula (XXVIII) with a compound of formula (XXIII) optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as JV,iV-dimethylformamide.
  • a compound of formula (XIV), wherein L 1 is a leaving group (such as halo, tosyl, mesyl etc.) and L 2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O) 2 Me etc.), may be prepared by the reaction of a compound of formula (XXIX) with a compound of formula (XXIII) optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as N.N-dimethylformamide.
  • a compound of formula (XVII), wherein L 1 is a leaving group (such as halo, tosyl, mesyl etc.) and L " is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O) 2 Me etc.) and R is a hydrogen or a Ci -4 alkyl group, may be prepared by the reaction of a compound of formula (XXX) with a compound of formula (XXIII) optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as ⁇ f JV-dimethylformamide.
  • a compound of formula (XIX), wherein L 1 is a leaving group (such as halo, tosyl, mesyl etc.) and L 2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O) 2 Me etc.), may be prepared by the reaction of a compound of formula (XXXI) with a compound of formula (XXIII) optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as ⁇ iV-dimethylformamide.
  • a compound of formula (XXI), wherein L 1 is a leaving group (such as halo, tosyl, mesyl etc.) and L 2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O) 2 Me etc.), may be prepared by the reaction of a compound of formula (XXXII) with a compound of formula (XXIII) optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as ⁇ N-dimethylformamide.
  • the R 2 group may be introduced at any stage initially as a carbocyclic or heterocyclic amine (optionally with the nitrogen protected, such protecting groups include but are not limited to nitro, terf-butoxy carbamate etc.) which can be transformed at a subsequent stage in the synthesis (after appropriate deprotection) to a sulphonamide by the reaction with a sulphonyl chloride (or other suitably activated species) in the presence of a suitable base, or other methods of forming a sulphonamide known in the literature.
  • protecting groups include but are not limited to nitro, terf-butoxy carbamate etc.
  • aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogen group.
  • modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulfinyl or alkylsulfonyl.
  • a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or te/Y-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a te/t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladiuni-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
  • the deprotection conditions for the above protecting groups will necessarily vaiy with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-buty ⁇ group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a base such as sodium hydroxide
  • a tert-buty ⁇ group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
  • the following assays can be used to measure the effects of the compounds of the present invention as mTOR kinase inhibitors, as PI3 kinase inhibitors, as inhibitors in vitro of the activation of PB kinase signalling pathways and as inhibitors in vitro of the proliferation of MDA-MB-468 human breast adenocarcinoma cells.
  • the assay used AlphaScreen technology (Gray et al. , Analytical Biochemistry, 2003, 313: 234-245) to determine the ability of test compounds to inhibit phosphorylation by recombinant mTOR.
  • a C-terminal truncation of mTOR encompassing amino acid residues 1362 to 2549 of mTOR (EMBL Accession No. L34075) was stably expressed as a FLAG-tagged fusion in HEK293 cells as described by Vilella-Bach et al, Journal of Biochemistry, 1999, 274, 4266-4272.
  • the HEK293 FLAG-tagged mTOR (1362-2549) stable cell line was routinely maintained at 37°C with 5% CO 2 up to a confluency of 70-90% in Dulbecco's modified Eagle's growth medium (DMEM; Invitrogen Limited, Paisley, UK Catalogue No. 41966- 029) containing 10% heat-inactivated foetal calf serum (FCS; Sigma, Poole, Dorset, UK, Catalogue No. F0392), 1% L-glutamine (Gibco, Catalogue No. 25030-024) and 2 mg/ml Geneticin (G418 sulfate; Invitrogen Limited, UK Catalogue No. 10131-027). Following expression in the mammalian HEK293 cell line, expressed protein was purified using the FLAG epitope tag using standard purification techniques.
  • Test compounds were prepared as 10 mM stock solutions in DMSO and diluted into water as required to give a range of final assay concentrations. Aliquots (2 ⁇ l) of each compound dilution were placed into a well of a Greiner 384- well low volume (LV) white polystyrene plate (Greiner Bio-one).
  • a 30 ⁇ l mixture of recombinant purified mTOR enzyme, 1 ⁇ M biotinylated peptide substrate (Biotin-Alix-Lys-Lys-Ala-Asn-Gln- Val-Phe-Leu-Gly-Phe-Thi--Tyr-Val-Ala-Pro-Ser-Val-Leu-Glu-Ser-Val-Lys-Glu-NH 2 ; Bachem UK Ltd), ATP (20 ⁇ M) and a buffer solution [comprising Tris-HCl pH7.4 buffer (50 mM), EGTA (0.1 mM), bovine serum albumin (0.5 mg/mL), DTT (1.25 mM) and manganese chloride (10 mM)] was agitated at room temperature for 90 minutes.
  • biotinylated peptide substrate Biotin-Alix-Lys-Lys-Ala-Asn-Gln- Val-Phe-Leu-Gly-
  • Control wells that produced a maximum signal corresponding to maximum enzyme activity were created by using 5% DMSO instead of test compound.
  • Control wells that produced a minimum signal corresponding to fully inhibited enzyme were created by adding EDTA (83 mM) instead of test compound.
  • EDTA 83 mM
  • These assay solutions were incubated for 2 hours at room temperature. Each reaction was stopped by the addition of 10 ⁇ l of a mixture of EDTA (50 mM), bovine serum albumin (BSA; 0.5 mg/mL) and Tris-HCl pH7.4 buffer (50 mM) containing p70 S6 Kinase (T389) 1 A5 Monoclonal Antibody (Cell Signalling Technology, Catalogue No. 9206B) and AlphaScreen Streptavidin donor and Protein A acceptor beads (200 ng; Perkin Elmer, Catalogue No. 6760002B and 6760137R respectively) were added and the
  • Phosphorylated biotinylated peptide is formed in situ as a result of mTOR mediated phosphorylation.
  • the phosphorylated biotinylated peptide that is associated io with AlphaScreen Streptavidin donor beads forms a complex with the p70 S6 Kinase (T389) 1A5 Monoclonal Antibody that is associated with Alphascreen Protein A acceptor beads.
  • the donor bead acceptor bead complex produces a signal that can be measured. Accordingly, the presence of mTOR kinase activity results in an assay signal. In the presence of an mTOR kinase inhibitor, signal is strength is reduced.
  • mTOR enzyme inhibition for a given test compound was expressed as an IC 50 value, (b) In Vitro PI3K Enzyme Assay
  • test compounds to inhibit phosphorylation by recombinant Type I PI3K enzymes of the lipid PI(4,5)P2.
  • DNA fragments encoding human PI3K catalytic and regulatory subunits were isolated from cDNA libraries using standard molecular biology and PCR cloning techniques. The selected DNA fragments were used to generate baculovirus expression
  • Type Ia human PI3K pi 10 isoforms (EMBL Accession Nos. HSU79143, S67334, Y10055 for pi 10a, pi lO ⁇ and pi 105 respectively) were sub-cloned into a pDESTIO vector (Invitrogen Limited, Fountain Drive, Paisley, UK).
  • the vector is a Gateway-adapted version of Fastbacl containing a 6-His epitope tag.
  • PI3K pi lO ⁇ isoform corresponding to amino acid residues 144-1102 (EMBL Accession No. X8336A) and the full length human p85 ⁇ regulatory subunit (EMBL Accession No. HSPl 3KIN) were also sub-cloned into pFastBacl vector containing a 6-His epitope tag.
  • the Type Ia pi 10 constructs were co-expressed with the p85 ⁇ regulatory subunit.
  • expressed proteins were purified using the His epitope tag using standard purification techniques.
  • Test compounds were prepared as 10 mM stock solutions in DMSO and diluted into water as required to give a range of final assay concentrations. Aliquots (2 ⁇ l) of each compound dilution were placed into a well of a Greiner 384- well low volume (LV) white polystyrene plate (Greiner Bio-one, Brunei Way, Stonehouse, Gloucestershire, UK Catalogue No. 784075). A mixture of each selected recombinant purified PI3K enzyme (15 ng), DiC8-PI(4,5)P2 substrate (40 ⁇ M; Cell Signals Inc., Kinnear Road, Columbus, USA, Catalogue No.
  • LV low volume
  • adenosine triphosphate (ATP; 4 ⁇ M)
  • a buffer solution [comprising Ti ⁇ s-HCl pH7.6 buffer (40 mM, 10 ⁇ l), 3-[(3- cholamidopropyl)dimethylammonio]-
  • Control wells that produced a minimum signal corresponding to maximum enzyme activity were created by using 5% DMSO instead of test compound.
  • Control wells that produced a maximum signal corresponding to fully inhibited enzyme were created by adding wortmannin (6 ⁇ M; Calbiochem / Merck Bioscience, Padge Road, Beeston, Nottingham, UK, Catalogue No. 681675) instead of test compound. These assay solutions were also agitated for 20 minutes at room temperature.
  • PI(3,4,5)P3 is formed in situ as a result of PI3K mediated phosphorylation of PI(4,5)P2.
  • the GST-Grpl PH domain protein that is associated with AlphaScreen Anti- GST donor beads forms a complex with the biotinylated PI(3,4,5)P3 that is associated with Alphascreen Streptavidn acceptor beads.
  • the enymatically-produced PI(3,4,5)P3 competes with biotinylated PI(3,4,5)P3 for binding to the PH domain protein.
  • the donor bead : acceptor bead complex produces a signal that can be measured.
  • PI3K enzme activity to form PI(3,4,5)P3 and subsequent competition with biotinylated PI(3,4,5)P3 results in a reduced signal.
  • signal strength is recovered.
  • This assay determines the ability of test compounds to inhibit phosphorylation of Serine 473 in Akt as assessed using Acumen Explorer technology (Acumen Bioscience Limited), a plate reader that can be used to rapidly quantitate features of images generated by laser-scanning.
  • a MDA-MB-468 human breast adenocarcinoma cell line (LGC Promochem, Teddiiigton, Middlesex, UK, Catalogue No. HTB-132) was routinely maintained at 37°C with 5% CO 2 up to a confluency of 70-90% in DMEM containing 10% heat-inactivated FCS and 1% L-glutamine.
  • the cells were detached from the culture flask using "Accutase' (Innovative Cell Technologies Inc., San Diego, CA, USA; Catalogue No. ATI 04) using standard tissue culture methods and resuspended in media to give 1.7xlO 5 cells per mL. Aliquots (90 ⁇ l) were seeded into each of the inner 60 wells of a black Packard 96 well plate (PerkinElmer, Boston, MA, USA; Catalogue No. 6005182) to give a density of -15000 cells per well. Aliquots (90 ⁇ l) of culture media were placed in the outer wells to prevent edge effects. The cells were incubated overnight at 37°C with 5% CO 2 to allow them to adhere.
  • test compounds were prepared as 10 niM stock solutions in DMSO and serially diluted as required with growth media to give a range of concentrations that were 10-fold the required final test concentrations. Aliquots (10 ⁇ l) of each compound dilution were placed in a well (in triplicate) to give the final required concentrations. As a minimum reponse control, each plate contained wells having a final concentration of 100 ⁇ M LY294002 (Calbiochem, Beeston, UK, Catalogue No. 440202). As a maximum response control, wells contained 1% DMSO instead of test compound. Following incubation, the contents of the plates were fixed by treatment with a 1.6% aqueous formaldehyde solution (Sigma, Poole, Dorset, UK, Catalogue No. F 1635) at room temperature for 1 hour.
  • the 'permeabilisation' buffer was removed and non-specific binding sites were blocked by treatment for 1 hour at room temperature of an aliquot (50 ⁇ l) of a blocking buffer consisting of 5% dried skimmed milk ['Marvel' (registered trade mark); Premier Beverages, Stafford, GB] in a mixture of PBS and 0.05% Tween-20.
  • the 'blocking' buffer was removed and the cells were incubated for 1 hour at room temperature with rabbit anti phospho-Akt (Ser473) antibody solution (50 ⁇ l per well; Cell Signalling, Hitchin, Herts, U.K., Catalogue No 9277) that had been diluted 1 :500 in 'blocking' buffer.
  • This assay determines the ability of test compounds to inhibit cell proliferation as assessed using Cellomics Array scan technology.
  • a MDA-MB-468 human breast adenocarcinoma cell line (LGC Promochem, Catalogue No. HTB- 132) was routinely maintained as described in Biological Assay (b) herein.
  • the proliferation assay the cells were detached from the culture flask using
  • Test compounds were prepared as 10 mM stock solutions in DMSO and serially diluted as required with growth media to give a range of test concentrations. Aliquots (50 ⁇ l) of each compound dilution were placed in a well and the cells were incubated for 2 days at 37 0 C with 5% CO 2 . Each plate contained control wells without test compound.
  • BrdU labelling reagent (Sigma, Catalogue No. B9285) at a final dilution of 1 :1000 was added and the cells were incubated for 2 hours at 37°C.
  • the medium was removed and the cells in each well were fixed by treatment with 100 ⁇ l of a mixture of ethanol and glacial acetic acid (90% ethanol, 5% glacial acetic acid and 5% water) for 30 minutes at room temperature.
  • the cells in each well were washed twice with PBS (100 ⁇ l).
  • Aqueous hydrochloric acid (2M, 100 ⁇ l) was added to each well. After 20 minutes at room temperature, the cells were washed twice with PBS.
  • Hydrogen peroxide (3%, 50 ⁇ l; Sigma, Catalogue No.
  • a 1 :1000 dilution of Hoechst stain (Molecular Probes, Catalogue No. H3570) was added. Each plate was washed in turn with PBS. Subsequently, PBS (100 ⁇ l) was added to each well and the plates were analysed using a Cellomics array scan to assess total cell number and number of BrdU positive cells. Fluorescence dose response data obtained with each compound were analysed and the degree of inhibition of MDA-MB-468 cell growth was expressed as an IC 5 Q value.
  • Example 4 the ICs 0 was measured on three occasions, the values were >134, 54, >698 ⁇ M, indicating this compound may be a selective mTOR inhibitor;
  • the compounds of the present invention are advantageous in that they possess pharmacological activity.
  • the compounds of the present invention modulate (in particular, inhibit) mTOR kinase and/or phosphatidylinositol-3 -kinase (PI3K) enzymes, such as the Class Ia PI3K enzymes (e.g. PBKalpha, PDKbeta and POKdelta) and the Class Ib PBK enzyme (PBKgamma).
  • PI3K phosphatidylinositol-3 -kinase
  • PBKgamma Class Ia PI3K enzymes
  • More particularly compounds of the present invention modulate (in particular, inhibit) mTOR kinase.
  • More particularly compounds of the present invention modulate (in particular, inhibit) one or more PI3K enzyme.
  • the inhibitory properties of compounds of formula (I) may be demonstrated using the test procedures set out herein and in the experimental section. Accordingly, the compounds of formula (I) may be used in the treatment (therapeutic or prophylactic) of conditions/diseases in human and non-human animals which are mediated by mTOR ldnase and/or one or more PD K enzyme(s), and in particular by mTOR kinase.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in association with a pharmaceutically acceptable diluent or carrier.
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixi
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • the amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
  • a formulation intended for oral administration to humans will generally contain, for example, from 1 mg to 1 g of active agent (more suitably from 1 to 250 mg, for example from 1 to 100 mg) compounded with an appropriate and convenient amount of excipients which may vaiy from about 5 to about 98 percent by weight of the total composition.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of formula I will naturally vaiy according to the nature and severity of the disease state, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
  • a daily dose in the range for example, 1 mg/kg to 100 mg/kg body weight is received, given if required in divided doses.
  • lower doses will be administered when a parenteral route is employed.
  • a dose in the range for example, 1 mg/kg to 25 mg/kg body weight will generally be used.
  • a dose in the range for example, 1 mg/kg to 25 mg/kg body weight will be used.
  • unit dosage forms will contain about 10 mg to 0.5 g of a compound of this invention.
  • mTOR kinase and the PI 3 K enzymes have roles in tumourigenesis as well as numerous other diseases.
  • the compounds of formula (I) possess potent anti-tumour activity which it is believed is obtained by way of inhibition of mTOR kinase and/or one or more of the PBK enzymes.
  • the compounds of the present invention are of value as anti-tumour agents.
  • the compounds of the present invention are of value as antiproliferative, apoptotic and/or anti-invasive agents in the containment and/or treatment of solid and/or liquid tumour disease.
  • the compounds of the present invention are expected to be useful in the prevention or treatment of those tumours which are sensitive to inhibition of mTOR and/or one or more of the PI3K enzymes such as the Class Ia PI3K enzymes and the Class Ib PI3K enzyme.
  • the compounds of the present invention are expected to be useful in the prevention or treatment of those tumours which are mediated alone or in part by mTOR and/or one or more of the PI3K enzymes such as the Class Ia PI3K enzymes and the Class Ib PI3K enzyme.
  • the compounds may thus be used to produce an mTOR enzyme inhibitory effect in a warm-blooded animal in need of such treatment.
  • Certain compounds may be used to produce an PI3K enzyme inhibitory effect in a warm-blooded animal in need of such treatment.
  • inhibitors of mTOR kinase and/or one or more PI3K enzymes should be of therapeutic value for the treatment of proliferative disease such as cancer and in particular solid tumours such as carcinoma and sarcomas and the leukaemias and lymphoid malignancies and in particular for treatment of, for example, cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate, and of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias [including acute lyniphoctic leukaemia (ALL) and chronic myelogenous leukaemia (CML)], multiple myeloma and lymphomas.
  • proliferative disease such as cancer and in particular solid tumours such as carcinoma
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein for use in the production of an apoptotic effect in a warm-blooded animal such as man.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein for the production of an apoptotic effect in a warm-blooded animal such as man.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the production of an apoptotic effect in a warm-blooded animal such as man.
  • a compound of formula (I) 5 or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in a warm-blooded animal such as man as an anti-invasive agent in the containment and/or treatment of proliferative disease such as cancer.
  • a method for producing an antiproliferative effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein.
  • a method for producing an anti-invasive effect by the containment and/or treatment of solid tumour disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the prevention or treatment of proliferative disease such as cancer in a warm-blooded animal such as man.
  • a method for the prevention or treatment of proliferative disease such as cancer in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein for use in the prevention or treatment of those tumours which are sensitive to inhibition of mTOR kinase and/or one or more PDK enzymes (such as the Class Ia enzymes and/or the Class Ib PI3K enzyme) that are involved in the signal transduction steps which lead to the proliferation, survival, invasiveness and migratory ability of tumour cells.
  • PDK enzymes such as the Class Ia enzymes and/or the Class Ib PI3K enzyme
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the prevention or treatment of those tumours which are sensitive to inhibition of mTOR kinase and/or one or more POK enzymes (such as the Class Ia enzymes and/or the Class Ib PI3K enzyme) that are involved in the signal transduction steps which lead to the proliferation, survival, invasiveness and migratoiy ability of tumour cells.
  • POK enzymes such as the Class Ia enzymes and/or the Class Ib PI3K enzyme
  • a method for the prevention or treatment of those tumours which are sensitive to inhibition of mTOR kinase and/or one or more PI3K enzymes such as the Class Ia enzymes and/or the Class Ib PI3K enzyme
  • PI3K enzymes such as the Class Ia enzymes and/or the Class Ib PI3K enzyme
  • administering comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein.
  • a mTOR kinase inhibitory effect and/or a PI3K enzyme inhibitory effect (such as a Class Ia PI3K enzyme or Class Ib PI3K enzyme inhibitory effect).
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in providing a mTOR kinase inhibitory effect and/or a PI3K enzyme inhibitory effect (such as a Class Ia PI3K enzyme or Class Ib PI3K enzyme inhibitory effect).
  • a method for providing a mTOR kinase inhibitory effect and/or a PI3K enzyme inhibitory effect which comprises administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, as defined herein.
  • a compound of formula I or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of cancer, inflammatory diseases, obstructive airways diseases, immune diseases or cardiovascular diseases.
  • leukaemias including ALL and CML
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof as defined herein in the manufacture of a medicament for use in the treatment of cancer, inflammatory diseases, obstructive airways diseases, immune diseases or cardiovascular diseases.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof as defined herein in the manufacture of a medicament for use in the treatment of of solid tumours such as carcinoma and sarcomas and the leukaemias and lymphoid malignancies.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the treatment of cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the treatment of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas.
  • a method for treating cancer, inflammatory diseases, obstructive airways diseases, immune diseases or cardiovascular diseases in a warm blooded animal such as man that is in need of such treatment which comprises administering an effective amount of a compound of formula
  • a method for treating solid tumours such as carcinoma and sarcomas and the leukaemias and lymphoid malignancies in a warm blooded animal such as man that is in need of such treatment which comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein.
  • a method for treating cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate in a warm blooded animal such as man that is in need of such treatment which comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein.
  • a method for treating cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas in a warm blooded animal such as man that is in need of such treatment which comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein.
  • the in vivo effects of a compound of formula (I) may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of formula (I).
  • the invention further relates to combination therapies wherein a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound of formula (I) is administered concurrently or sequentially or as a combined preparation with another treatment of use in the control of oncology disease.
  • the treatment defined herein may be applied as a sole therapy or may involve, in addition to the compounds of the invention, conventional surgery or radiotherapy or chemotherapy. Accordingly, the compounds of the invention can also be used in combination with existing therapeutic agents for the treatment of cancer.
  • Suitable agents to be used in combination include :-
  • antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea and gemcitabine); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like
  • anti-invasion agents for example c-Src kinase family inhibitors like 4-(6-chloro- 2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-l-yl)ethoxy]-5-tetrahydropyran- 4-yloxyquinazoline (AZD0530; International Patent Application WO 01/94341) and N-(2-chloro-6-methylphenyl)-2- ⁇ 6-[4-(2-hydroxyethyl)piperazin-l-yl]-2- methylpyrimidin-
  • c-Src kinase family inhibitors like 4-(6-chloro- 2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-l-yl)ethoxy]-5-tetrahydropyran- 4-yloxyquinazoline (AZD0530; International Patent Application WO 01/94341) and N-(2-chloro-6-methylphenyl)-2
  • inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [HerceptinTM] and the anti-erbBl antibody cetuximab [C225]); such inhibitors also include, for example, tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (AvastinTM) and VEGF receptor tyrosine kinase inhibitors such as
  • vascular damaging agents such as combretastatin A4 and compounds disclosed in
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense agent;
  • gene therapy approaches including approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
  • immunotherapeutic approaches including ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transf
  • HPLC Agilent 1100 or Waters Alliance HT (2790 & 2795)
  • Mobile phase A Water
  • Method A - Instrument: Agilent 1100; Column: Kromasil Cl 8 reversed-phase silica, 100 x 3 mm, 5 ⁇ m particle size; Solvent A: 0.1% TF A/water, Solvent B: 0.08%
  • Method B - Instrument: Agilent 1100; Column: Waters 'Xterra' C8 reversed- phase silica, 100 x 3 mm, 5 ⁇ m particle size; Solvent A: 0.015M ammonia in water,
  • Solvent B acetonitrile; Flow Rate: 1 ml/min, Solvent Gradient: 10-100% Solvent B for 20 minutes followed by 100% Solvent B for 1 minute; Absorption Wavelength: 220, 254 and
  • DIPEA N,iV-diisopropylethylamine 0 DBU l,8-diazabicyclo[5.4.0]undec-7-ene;
  • RT room temperature (approximately 17 to 25 0 C); tR retention time; m/z mass/charge ratio.
  • Example 1 ⁇ / -[2-(Hvdroxymethv ⁇ -4-[4-(methylsulfonylmethyI)-6-tnorpholin-4-yl- Pyrimidin-2-yllphenyllmethanesulfonamide
  • Methyl 5-biOmo-2-methanesulfonamido-benzoate (1.34 g) was dissolved in THF (30 niL) and cooled to O 0 C.
  • Lithium aluminium hydride (8.7 niL, IM solution THF) was added slowly to the solution over 15 minutes. The reaction was allowed to warm to room temperature and stir for 2 hours before being quenched with water and filtered. The solution was concentrated in vacuo and the residue chromatographed on silica, eluting with 2.5% methanol in DCM, to give the desired material as a white solid (333 mg).
  • Methyl-2-amino-5-bromobenzoate (1 g) was dissolved in THF (20 mL) and triethylamine (3.6 mL). The mixture was cooled to O 0 C in an ice bath and methanesulfonyl chloride (1 mL) was added slowly. The reaction was allowed to stir at O 0 C for 15 minutes then left too stir for 19 hours at room temperature. The reaction was quenched with water (10 mL) and concentrated in vacuo. The reaction was partitioned between ethyl acetate (50 mL) and water (50 mL), the organics dried (MgSO 4 ), filtered, and concentrated in vacuo to give the desired material (1.68 g) as a white solid.
  • 6-(Chloromethyl)uracil (10.00 g) was dissolved in DMF (300 mL) and methanesulphinic acid sodium salt (7.64 g) added. The reaction was heated at 125 0 C for 1 hour. The reaction was allowed to cool, filtered and the filtrate concentrated in vacuo to give the desired material as a yellow solid (12.72 g).
  • Test (a) average IC 50 6.8 ⁇ M.
  • the starting material [4-[4-(methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidin-2- yl]phenyl]methanamine was prepared as follows. r4-r4-(Methylsulfonylmethyl)-6-mo ⁇ holin-4-yl-pyrimidin-2-yllphenyl]methananiine
  • the mixture was transferred to an SCX column, previously eluted with methanol.
  • 6-(ChloiOmethyl)-2-methylsulfanyl-py ⁇ midin-4-ol (19.07 g, 100 mmol) was suspended in acetonitrile (400 ml). To this stirring suspension was added methanesulphinic acid sodium salt (12.255g, 120 mmol) and DMF (100 ml). The reaction was then heated to 100° C to give a dark suspension and monitored by LCMS. Once complete, the solvents were removed and the resultant product added to 1 : 1 MeOH:DCM (200 ml) and acidified with acetic acid (10 ml).
  • Example 3a Test (a) average IC 5 0 1.4 ⁇ M.
  • Example 3b Test (a) average IC 50 4 ⁇ M.
  • Example 3c Test (a) average IC 50 6 ⁇ M.
  • Example 3d Test (a) average IC 50 7.1 ⁇ M.
  • Triethylamine (0.038 mL, 0.27 rnmol) was added to a solution of [4-[4-[(3S>3- methylmoipholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]phenyl]methanamine (100 mg, 0.27 mmol) in DCM (5 mL).
  • Methanesulphonyl chloride (0.021 mL, 0.27 mniol) was added and the reaction stirred at room temperature for 2 hours. The organics were washed with water (5 mL), dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified on silica, eluting with 0-5% methanol in DCM, to give the desired material as a white solid (90 mg).
  • 2,4-Dichloro-6-(methylsulfonylmethyl)pyrimidine (30 g, 0.13 mol) was dissolved in dichloromethane and stirred (under nitrogen) at -5°C. Triethylamine (17.4 mL, 0.13 mol) was added to give a clear brown solution. (35)-3-Methylmorpholine was dissolved in dichloromethane and added dropwise keeping the reaction below -5°C. The cooling bath was then removed and the mixture stirred for 1 hour. The reaction mixture was heated at reflux for 2 hours, then the reaction mixture was washed with water, dried then evaporated. The crude material was purified by preparative HPLC to give the desired material as a solid (19.3 g).

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Abstract

A compound of formula (I) or a pharamaceutically acceptable salt thereof, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, for example in the treatment of proliferative disease such as cancer and particularly in disease mediated by an mTOR kinase and/or one or more PI3K enzyme.

Description

MORPHOLINO PYRIMIDINE DERIVATIVES USEFUL IN THE TREATMENT OF
PROLIFERATIVE DISORDERS
The present invention relates to morpholino pyrimidine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, for example in the treatment of proliferative disease such as cancer and particularly in
5 disease mediated by an mTOR kinase and/or one or more PI3K enzyme.
It is now well understood that deregulation of oncogenes and tumour-suppressor genes contributes to the formation of malignant tumours, for example by way of increased cell proliferation or increased cell survival. It is also known that signalling pathways mediated by the PBK/mTOR families have a central role in a number of cell processes io including proliferation and survival, and deregulation of these pathways is a causative factor in a wide spectrum of human cancers and other diseases.
The mammalian target of the macrolide antibiotic Rapamycin (sirolimus) is the enzyme mTOR. This enzymes belongs to the phosphatidylinositol (PI) kinase-related kinase (PIKK) family of protein kinases, which also includes ATM, ATR, DNA-PK and
I5 hSMG-1. mTOR, like other PIKK family members, does not possess detectable lipid kinase activity, but instead functions as a serine/threonine kinase. Much of the knowledge of mTOR signalling is based upon the use of Rapamycin. Rapamycin first binds to the 12 kDa immunophilin FK506-binding protein (FKBP 12) and this complex inhibits mTOR signalling (Tee and Blenis, Seminars in Cell and Developmental Biology, 2005, 16, 29-
20 37). The mTOR protein consists of a catalytic kinase domain, an FKBP12-Rapamycin binding (FRB) domain, a putative repressor domain near the C-terminus and up to 20 tandemly-repeated HEAT motifs at the iV-terminus, as well as FRAP-ATM-TRRAP (FAT) and FAT C-terminus domain (Huang and Houghton, Current Opinion in Pharmacology, 2003, 3, 371-377).
25 mTOR kinase is a key regulator of cell growth and has been shown to regulate a wide range of cellular functions including translation, transcription, mRNA turnover, protein stability, actin cytoskeleton reorganisation and autophagy (Jacinto and Hall, Nature Reviews Molecular and Cell Biology, 2005, 4, 117-126). mTOR kinase integrates signals from growth factors (such as insulin or insulin-like growth factor) and nutrients
30 (such as amino acids and glucose) to regulate cell growth. mTOR kinase is activated by growth factors through the PI3K-Akt pathway. The most well characterised function of mTOR kinase in mammalian cells is regulation of translation through two pathways, namely activation of ribosomal S6K1 to enhance translation of mRNAs that bear a 5'- terminal oligopyrimidine tract (TOP) and suppression of 4E-BP1 to allow CAP-dependent mRNA translation.
Generally, investigators have explored the physiological and pathological roles of mTOR using inhibition with Rapamycin and related Rapamycin analogues based on their specificity for mTOR as an intracellular target. However, recent data suggests that Rapamycin displays variable inhibitory actions on mTOR signalling functions and suggest that direct inhibition of the mTOR kinase domain may display substantially broader anticancer activities than that achieved by Rapamycin (Edinger et al, Cancer Research, 2003, 63, 8451-8460). For this reason, potent and selective inhibitors of mTOR kinase activity would be useful to allow a more complete understanding of mTOR kinase function and to provide useful therapeutic agents.
There is now considerable evidence indicating that the pathways upstream of mTOR, such as the PI3K. pathway, are frequently activated in cancer (Vivanco and Sawyers, Nature Reviews Cancer, 2002, 2, 489-501 ; Bjornsti and Houghton, Nature Reviews Cancer, 2004, 4, 335-348; Inoki et al, Nature Genetics, 2005, 37, 19-24). For example, components of the PI3K pathway that are mutated in different human tumours include activating mutations of growth factor receptors and the amplification and/or overexpression of PI3K and Akt. In addition there is evidence that endothelial cell proliferation may also be dependent upon mTOR signalling. Endothelial cell proliferation is stimulated by vascular endothelial cell growth factor (VEGF) activation of the PI3K-Akt-mTOR signalling pathway (Dancey, Expert Opinion on Investigational Drugs, 2005, 14, 313-328). Moreover, mTOR kinase signalling is believed to partially control VEGF synthesis through effects on the expression of hypoxia-inducible factor- 1 α (HIF- 1 α) (Hudson et al. , Molecular and Cellular Biology, 2002, 22, 7004-7014). Therefore, tumour angiogenesis may depend on mTOR kinase signalling in two ways, through hypoxia-induced synthesis of VEGF by tumour and stromal cells, and through VEGF stimulation of endothelial proliferation and survival through PI3K-Akt-mTOR signalling. These findings suggest that pharmacological inhibitors of mTOR kinase should be of therapeutic value for treatment of the various foπns of cancer comprising solid tumours such as carcinomas and sarcomas and the leukaemias and lymphoid malignancies. In particular, inhibitors of niTOR kinase should be of therapeutic value for treatment of, for example, cancer of the breast, colorectum, lung (including small cell lung cancer, non- small cell lung cancer and bronchioalveolar cancer) and prostate, and of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovaiy , pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas.
In addition to tumourigenesis, there is evidence that mTOR kinase plays a role in an array of hamartoma syndromes. Recent studies have shown that the tumour suppressor proteins such as TSCl, TSC2, PTEN and LKBl tightly control mTOR kinase signalling. Loss of these tumour suppressor proteins leads to a range of hamartoma conditions as a result of elevated mTOR kinase signalling (Tee and Blenis, Seminars in Cell and Developmental Biology, 2005, 16, 29-37). Syndromes with an established molecular link to dysregulation of mTOR kinase include Peutz-Jeghers syndrome (PJS), Cowden disease, Bannayan-Riley-Ruvalcaba syndrome (BRRS), Proteus syndrome, Lhermitte-Duclos disease and Tuberous Sclerosis (TSC) (Inoki et al, Nature Genetics, 2005, 37, 19-24). Patients with these syndromes characteristically develop benign hamartomatous tumours in multiple organs.
Recent studies have revealed a role for mTOR kinase in other diseases (Easton & Houghton, Expert Opinion on Therapeutic Targets, 2004, 8, 551-564). Rapamycin has been demonstrated to be a potent immunosuppressant by inhibiting antigen-induced proliferation of T cells, B cells and antibody production (Sehgal, Transplantation Proceedings, 2003, 35, 7S-14S) and thus mTOR kinase inhibitors may also be useful immunosuppressives. Inhibition of the kinase activity of mTOR may also be useful in the prevention of restenosis, that is the control of undesired proliferation of normal cells in the vasculature in response to the introduction of stents in the treatment of vasculature disease (Morice et al, New England Journal of Medicine, 2002, 346, 1773-1780). Furthermore, the Rapamycin analogue, everolimus, can reduce the severity and incidence of cardiac allograft vasculopathy (Eisen et al. New England Journal of Medicine, 2003, 349, 847- 858). Elevated mTOR kinase activity has been associated with cardiac hypertrophy, which is of clinical importance as a major risk factor for heart failure and is a consequence of increased cellular size of cardiomyocytes (Tee & Blenis, Seminars in Cell and Developmental Biology, 2005, 16, 29-37). Thus mTOR kinase inhibitors are expected to be of value in the prevention and treatment of a wide variety of diseases in addition to cancer.
It is also believed that a number of these morpholino pyrimidine derivatives may have inhibitory activity against the phosphatidylinositol (PI) 3-kinases family of kinases. Phosphatidylinositol (PI) 3-kinases (PDKs) are ubiquitous lipid kinases that function both as signal transducers downstream of cell-surface receptors and in constitutive intracellular membrane and protein trafficking pathways. All PBKs are dual- specificity enzymes with a lipid kinase activity that phosphorylates phosphoinositides at the 3-hydroxy position, and a less well characterised protein kinase activity. The lipid products of PI3K-catalysed reactions comprising phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3], phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2] and phosphatidylinositol 3 -monophosphate [PI(3)P] constitute second messengers in a variety of signal transduction pathways, including those essential to cell proliferation, adhesion, survival, cytoskeletal rearrangement and vesicle trafficking. PI(3)P is constitutively present in all cells and its levels do not change dramatically following agonist stimulation. Conversely, PI(3,4)P2 and PI(3,4,5)P3 are nominally absent in most cells but they rapidly accumulate on agonist stimulation.
The downstream effects of PI3K-produced 3-phosphoinositide second messengers are mediated by target molecules containing 3-phosphoinositide binding domains such as the pleckstrin homology (PH) domain and the recently identified FYVE and phox domains.
Well-characterised protein targets for PI3K include PDKl and protein kinase B (PKB). In addition, tyrosine kinases like Btk and Itk are dependent on PI3K activity.
The PI3K family of lipid kinases can be classified into three groups according to their physiological substrate specificity (Vanhaesebroeck et al , Trends in Biol. Sci., 1997, 22, 267). Class III PI3K enzymes phosphorylate PI alone. In contrast, Class II PI3K enzymes phosphorylate both PI and PI 4-phosphate [PI(4)P]. Class I PI3K enzymes phosphorylate PI, PI(4)P and PI 4,5-bisphosphate [PI(4,5)P2], although only PI(4,5)P2 is believed to be the physiological cellular substrate. Phosphorylation of PI(4,5)P2 produces the lipid second messenger PI(3,4,5)P3. More distantly related members of the lipid kinase superfamily are Class IV kinases such as mTOR (discussed above) and DNA- dependent kinase that phosphorylate serine/tlireonine residues within protein substrates. The most studied and understood of the PI3K lipid kinases are the Class I PI3K enzymes.
Class I PI3Ks are heterodimers consisting of a pi 10 catalytic subunit and a regulatory subunit. The family is further divided into Class Ia and Class Ib enzymes on the basis of regulatory partners and the mechanism of regulation. Class Ia enzymes consist of three distinct catalytic subunits (pi 10a, pi lOβ and pi lOδ) that dimerise with five distinct regulatory subunits (p85α, p55α, p50α, p85β and p55γ), with all catalytic subunits being able to interact with all regulatory subunits to form a variety of heterodimers. Class Ia PBKs are generally activated in response to growth factor- stimulation of receptor tyrosine kinases via interaction of their regulatory subunit SH2 domains with specific phospho-tyrosine residues of activated receptor or adaptor proteins such as IRS-I . Both pi 10a and pi lOβ are constitutively expressed in all cell types, whereas pi lOδ expression is more restricted to leukocyte populations and some epithelial cells. In contrast, the single Class Ib enzyme consists of a pi lOγ catalytic subunit that interacts with a pi 01 regulatory subunit. Furthermore, the Class Ib enzyme is activated in response to G-protein coupled receptor systems (GPCRs) and its expression appears to be limited to leukocytes and cardiomyocytes.
There is now considerable evidence indicating that Class Ia PI3K enzymes contribute to tumourigenesis in a wide variety of human cancers, either directly or indirectly (Vivanco and Sawyers, Nature Reviews Cancer, 2002, 2, 489-501). For example, the pi 10a subunit is amplified in some tumours such as those of the ovary (Shayesteh et al. Nature Genetics, 1999, 21, 99-102) and cervix (Ma et al, Oncogene, 2000, 19, 2739-2744). More recently, activating mutations within the catalytic site of the pi 10a catalytic subunit have been associated with various other tumours such as those of the colorectal region and of the breast and lung (Samuels et al, Science, 2004, 304, 554). Tumour-related mutations in the p85α regulatory subunit have also been identified in cancers such as those of the ovaiy and colon (Philp et al., Cancer Research, 2001, 61, 7426-7429). In addition to direct effects, it is believed that activation of Class Ia PI3Ks contributes to tumourigenic events that occur upstream in signalling pathways, for example by way of ligand-dependent or ligand-independent activation of receptor tyrosine kinases, GPCR systems or integrins (Vara et al, Cancer Treatment Reviews, 2004, 30, 193-204). Examples of such upstream signalling pathways include over-expression of the receptor tyrosine kinase erbB2 in a variety of tumours leading to activation of PI3K- mediated pathways (Harari et ah, Oncogene, 2000, 19, 6102-6114) and over-expression of the ras oncogene (Kauffmann-Zeh et α/., Nature, 1997, 385, 544-548). In addition, Class Ia PI3Ks may contribute indirectly to tumourigenesis caused by various downstream signalling events. For example, loss of the effect of the PTEN tumour-suppressor phosphatase that catalyses conversion of PI(3,4,5)P3 back to PI(4,5)P2 is associated with a very broad range of tumours via deregulation of PI3 K- mediated production of PI(3,4,5)P3 (Simpson and Parsons, Exp. Cell Res., 2001, 264, 29-41). Furthermore, augmentation of the effects of other PI3K-mediated signalling events is believed to contribute to a variety of cancers, for example by activation of Akt (Nicholson and Anderson, Cellular Signalling, 2002, 14, 381-395).
In addition to a role in mediating proliferative and survival signalling in tumour cells, there is evidence that Class Ia PI3K enzymes contribute to tumourigenesis in tumour-associated stromal cells. For example, PI3K signalling is known to play an important role in mediating angiogenic events in endothelial cells in response to pro- angiogenic factors such as VEGF (Abid et ah, Arterioscler. Tliromb. Vase. Biol., 2004, 24, 294-300). As Class I PI3K enzymes are also involved in motility and migration (Sawyer, Expert Opinion Investig. Drugs, 2004, 13, 1-19), PI3K enzyme inhibitors should provide therapeutic benefit via inhibition of tumour cell invasion and metastasis. In addition, Class I PI3K enzymes play an important role in the regulation of immune cells contributing to pro-tumourigenic effects of inflammatory cells (Coussens and Werb, Nature, 2002, 420, 860-867).
These findings suggest that pharmacological inhibitors of Class I PI3K enzymes will be of therapeutic value for the treatment of various diseases including different forms of the disease of cancer comprising solid tumours such as carcinomas and sarcomas and the leukaemias and lymphoid malignancies. In particular, inhibitors of Class I PI3K enzymes should be of therapeutic value for treatment of, for example, cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate, and of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas.
POKγ, the Class Ib PI3K, is activated by GPCRs, as was finally demonstrated in mice lacking the enzyme. Thus, neutrophils and macrophages derived from PDKγ- deficient animals failed to produce PI(3,4,5)P3 in response to stimulation with various chemotactic substances (such as IL-8, C5a, fMLP and MIP-Ia), whereas signalling through protein tyrosine kinase-coupled receptors to Class Ia PI3Ks was intact (Hirsch et al, Science, 2000, 287(5455), 1049-1053; Li et al, Science, 2002, 287(5455), 1046-1049; Sasaki et al., Science 2002, 287(5455), 1040-1046). Furthermore, PI(3,4,5)P3-mediated phosphorylation of PKB was not initiated by these GPCR ligands in PI3Kγ-null cells. Taken together, the results demonstrated that, at least in resting haematopoietic cells, PI3Kγ is the sole PI3K isoform that is activated by GPCRs in vivo. When murine bone marrow-derived neutrophils and peritoneal macrophages from wild- type and POKγ"7" mice were tested in vitro, a reduced, but not completely abrogated, performance in chemotaxis and adherence assays was observed. However, this translated into a drastic impairment of IL-8 driven neutrophil infiltration into tissues (Hirsch et al, Science, 2000, 287(5455), 1049-1053.). Recent data suggest that PI3Kγ is involved in the path finding process rather than in the generation of mechanical force for motility, as random migration was not impaired in cells that lacked PI3Kγ (Hannigan et a!., Proc. Nat. Acad, of Sciences of U.S.A., 2002, 99(6), 3603-8). Data linking PDKγto respiratory disease pathology came with the demonstration that PI3Kγ has a central role in regulating endotoxin-induced lung infiltration and activation of neutrophils leading to acute lung injury (Yum et al, J. Immunology, 2001, 167(11), 6601-8). The fact that although POKγ is highly expressed in leucocytes, its loss seems not to interfere with haematopoiesis, and the fact that POKγ-null mice are viable and fertile further implicates this POK isoform as a potential drug target. Work with knockout mice also established that POKγ is an essential amplifier of mast cell activation (Laffargue et al, Immunity, 2002, 16(3), 441-451).
Thus, in addition to tumourigenesis, there is evidence that Class I POK enzymes play a role in other diseases (Wymann et al, Trends in Pharmacological Science, 2003, 24, 366-376). Both Class Ia POK enzymes and the single Class Ib enzyme have important roles in cells of the immune system (Koyasu, Nature Immunology, 2003, 4, 313-319) and thus they are therapeutic targets for inflammatory and allergic indications. Recent reports demonstrate that mice deficient in PI3Kγ and PDKδ are viable, but have attenuated inflammatory and allergic responses (AIi et oh, Nature, 2004, 431(7011), 1007-11). Inhibition of PI3K is also useful to treat cardiovascular disease via anti-inflammatory effects or directly by affecting cardiac myocytes (Prasad et al, , Trends in Cardiovascular Medicine, 2003, 13, 206-212). Thus, inhibitors of Class I PI3K enzymes are expected to be of value in the prevention and treatment of a wide variety of diseases in addition to cancer.
Several compounds that inhibit PI3Ks and phosphatidylinositol (PI) kinase-related kinase (PBKKs) have been identified, including wortmannin and the quercetin derivative LY294002. These compounds are reasonably specific inhibitors of POKs and PI3KKs over other kinases but they lack potency and display little selectivity within the PI3K families.
Accordingly, it would be desirable to provide further effective mTOR and/or PI3K inhibitors for use in the treatment of cancer, inflammatory or obstructive airways diseases, immune or cardiovascular diseases.
Morpholino pyrimidine derivatives and PI3K inhibitors are known in the art. International Patent Application WO 2004/048365 discloses compounds that possess PI3K enzyme inhibitory activity and are useful in the treatment of cancer. These compounds are arylamino- and heteroarylamino-substituted pyrimidines which differ from the compounds of the present invention with respect to their aiy lamino- and heteroarylamino substituents. These substituents are not equivalent to the -XR1 substituents of the present invention. Inhibitors of PI3K activity useful in the treatment of cancer are also disclosed in European Patent Application 1 277 738 which mentions 4- morpholino-substituted bicyclic heteroaryl compounds such as quinazoline and pyrido [3 ,2-d] pyrimidine derivatives and 4-morpholino-substituted tricyclic heteroaryl compounds but not monocyclic pyrimidine derivatives.
A number of compounds such as 4-moφholin-4-yl-6-(phenylsulfonylmethyl)-2- pyridin-4-yl-pyrimidine and 4- {6-[(phenylsulfonyl)methyl]-2-pyridin-2-ylpyrimidin-4- yl}morpholine have been registered in the Chemical Abstracts database but no utility has been indicated and there is no suggestion that these compounds have mTOR and/or PI3K inhibitory activity or useful therapeutic properties. Surprisingly, we have found that certain morpholino pyrimidine derivatives possess useful therapeutic properties. Without wishing to be bound by theoretical constraints, it is believed that the therapeutic usefulness of the derivatives is derived from their inhibitory activity against mTOR kinase and/or one or more PI3K enzyme (such as the Class Ia enzyme and/or the Class Ib enzyme). Because signalling pathways mediated by the PI3K/mTOR families have a central role in a number of cell processes including proliferation and survival, and because deregulation of these pathways is a causative factor in a wide spectrum of human cancers and other diseases, it is expected that the derivatives will be therapeutically useful. In particular, it is expected that the derivatives will have antiproliferative and/or apoptotic properties which means that they will be useful in the treatement of proliferative disease such as cancer. The compounds of the present invention may also be useful in inhibiting the uncontrolled cellular proliferation which arises from various non-malignant diseases such as inflammatory diseases, obstructive airways diseases, immune diseases or cardiovascular diseases. Generally, the compounds of the present invention possess potent inhibitory activity against mTOR kinase but the compound may also possess potent inhibitory activity against one or more PDK enzyme (such as the Class Ia enzyme and/or the Class Ib enzyme).
In accordance with an aspect of the present invention, there is provided a compound of formula (I)
Figure imgf000010_0001
formula (I) or a pharmaceutically acceptable salt thereof; wherein m is O, 1, 2, 3 or 4; 1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is CR8; X is a linker group selected from -CR4=CR5-, -CR4^CR5CR6R7-, -CR6R7CR5=CR4-, -C≡C-, -C≡CCR6R7-, -CRόR7C≡C-, -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-, -S(O)2CR0R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7-, -NR4S(O)2CR6R7-, -S(O)2NR4CR6R7-, -C(O)NR4-, -NR4C(O)-, -NR4C(O)NR5-, -S(O)2NR4- and -NR4S(O)2-;
R1 is a group selected from hydrogen, Ci-δalkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, carbocyclylCi-6alkyl, heterocyclyl and heterocyclylCi-6alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R9, -OR , -SR9, -SOR9, -SO2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2R10, -NR9CONR10R15, -NR9COCONR10R15 and -NR9SO2R10;
R2 is a group selected from Ci-6alkyl, carbocyclyl and heterocyclyl which group is substituted by -NR17SO2R18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -SR11, -SOR11, -SO2R1 1, -COR11, -CO2R11, -CONR11R12, -NR11R12, -NR11COR12, and -NR1 1COCONR12R16; each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -SR13, -SOR13, -SO2R13, -COR13, -CO2R13, -CONR13R14, -NR13R14, -NR13COR14, -NR13CO2R14 and -NR13SO2R14; R4 and R5 are independently hydrogen or Ci^alkyl; or R1 and R4 together with the atom or atoms to which they are attached form a 5- to 10- membered carbocyclic or heterocyclic ring wherein 1 , 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci^alkyl, Ci-balkoxy, haloCi- 6alkyl, haloQ-όalkoxy, hydroxyCi-6alkyl, hydroxyCi-ealkoxy, Ci.6alkoxyCi-6alkyl, Ci. t,alkoxyCi-balkoxy, amino, C1-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-όalkyl, (Ci. balkyl)aminoCi-6alkyl, bis(C1-6alkyl)aminoCi.6alkyl, cyanoCi-όalkyl, C[.6alkylsulfonyl, Q- ealkylsulfonylamino, C i-6alkylsulfonyl(Ci -6alkyl)amino, sulfamoyl, C i -βalkylsulfamoyl, bis(Ci.6alkyl)sulfamoyl, Ci.balkanoylamino, Ci.6alkanoyl(Ci-6alkyl)amino, carbamoyl, Ci- ύalkylcarbamoyl and bis(Ci.6alkyl)carbamoyl; R6 and R7 are independently selected from hydrogen, halo, cyano, nitro and Ci.6alkyl; R8 is selected from hydrogen, halo, cyano and Ci-6alkyl;
R9 and R10 are independently hydrogen or a group selected from C^aHcyl, carbocyclyl, carbocyclylC]-6alkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally -U-
substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci.6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi.0alkoxy, hydroxyCt.δalkyl, hydiOxyCi-6alkoxy, Ci-balkoxyCi-ealkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-όalkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-6alkyl)aminoCι.6alkyl, bis(Ci.6alkyl)aminoCi-6alkyl,
Figure imgf000012_0001
Ci-βalkylsulfonyl, Ci.6alkylsulfonylamino, Ci-0alkylsulfonyl(Ci-6alkyl)aniino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci-6alkanoyl(C|. 6alkyl)amino, carbamoyl, Ci^alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R11, R12 and R17 are independently hydrogen or a group selected from Ci-6alkyl, carbocyclyl, carbocyclylCi.6alkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Cugalkyl, Ci-6alkoxy, haloCi-galkyl, haloCi-ealkoxy, hydroxyCi.6alkyl, hydroxyCi-6alkoxy, Ci.6alkoxyCι.6alkyl, Ci-6alkoxyCi-balkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-t)alkyl, (Ci-6alkyl)aminoCi-6alkyl, bis(Ci-6alkyl)aminoCi. 6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-όalkanoylamino, Ci-6alkanoyl(Ci. 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R13, R14, R15, R16 and R18 are independently hydrogen or a group selected from C1-6alkyl, carbocyclyl, carbocyclylCi-6alkyl, heterocyclyl and heterocyclylCi-βalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci.6alkoxy, haloCi-6alkyl, haloCi.balkoxy, hydroxyCi-balkyl, hydiOxyC],6alkoxy,
Figure imgf000012_0002
Ci-βalkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-ealkyl, (Ci-6alkyl)aminoCi.6alkyl, bis(Ci.6alkyl)aminoCi- όalkyl, cyanoCi^alkyl, Ci-βalkylsulfonyl, Ci.6alkylsulfonylamino, Ci.6alkylsulfonyl(Ci- Oalkyl)amino, sulfamoyl, d-όalkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-ealkanoylamino, Ci-6alkanoyl(Ci-6alkyl)amino, carbamoyl,
Figure imgf000012_0003
and Ws(C1. 6alkyl)carbamoyl, for use as a medicament in the treatment of proliferative disease.
In accordance with another aspect of the present invention, there is provided a compound of formula (I)
Figure imgf000013_0001
formula (I) or a pharmaceutically acceptable salt thereof; wherein m is O, 1, 2, 3 or 4;
5 1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is CR8;
X is a linker group selected from -CR4=CR5-, -CR4=CR5CR6R7-, -CR6R7CR5^CR4-, -C=C-, -C≡CCR6R7-, -CR6R7C=C-, -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-, -S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7-, io -NR4S(O)2CR6R7-, -S(O)2NR4CR6R7-, -C(O)NR4-, -NR4C(O)-, -NR4C(O)NR5-, -S(O)2NR4- and -NR4S(O)2-;
R1 is a group selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, carbocyclylCi-6alkyl, heterocyclyl and heterocyclylCi-6alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R9, -OR9,
I5 -SR9, -SOR9, -SO2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2R10, -NR9CONR10R15, -NR9COCONR10R15 and -NR9SO2R10; or X-R1 is -CR6R7OH;
R2 is a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is substituted by -NR17SO2R18 and optionally substituted by one or more substituent group
20 independently selected from halo, cyano, nitro, -R11, -OR11, -SR11, -SOR11, -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR11R12, -NR11COR12, and -NR11COCONR12R16; each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -SR13, -SOR13, -SO2R13, -COR13, -CO2R13, -CONR13R14, -NR13R14, -NR13COR14, -NR13CO2R14 and -NR13SO2R14;
2S R4 and R5 are independently hydrogen or Ci-όalkyl; or R1 and R4 together with the atom or atoms to which they are attached form a 5- to 10- membered carbocyclic or heterocyclic ring wherein 1 , 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, Ci-6alkoxy, haloCi- 6alkyl, haloCi-όalkoxy, hydroxyCi-6alkyl, hydroxyCi.6alkoxy, Cι.6alkoxyCi..6alkyl, Ci- balkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-ealkyl, (Ci- 6alkyl)aminoCi-0alkyl, bis(Ci-6alkyl)aminoCi.6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci- 6alkylsulfonylamino, Ci.6alkylsulfonyl(Ci-6alkyl)amino, sulfamoyl,
Figure imgf000014_0001
bis(Ci-balkyl)sulfamoyl, Ci-6alkanoylamino, Ci-balkanoyl(Cι-6alkyl)amino, carbamoyl, Q- 6alkylcarbamoyl and bis(C[-6alkyl)carbamoyl; R6 and R7 are independently selected from hydrogen, halo, cyano, nitro and Ci.<,alkyl; R is selected from hydrogen, halo, cyano and C^alkyl;
R9 and R10 are independently hydrogen or a group selected from Ci-6alkyl, carbocyclyl, carbocyclylCi-όalkyl, heterocyclyl and heterocyclylCi.6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, Ci-6alkoxy, haloCi-όalkyl, haloCi-galkoxy, hydroxyCi-όalkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-ealkylamino, bis(Ci-6alkyl)amino, aminoCi-όalkyl, (Ci-6alkyl)aminoCi.6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-balkylsulfonylamino, Ci.6alkylsulfonyl(Ci-6alkyl)amino, sulfamoyl, Ci-salkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000014_0002
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(d-6alkyl)carbamoyl; R11, R12 and R17 are independently hydrogen or a group selected from Ci-balkyl, carbocyclyl, carbocyclylCi.6alkyl, heterocyclyl and heterocyclylCi-ealkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, Ci-6alkoxy, haloCi-6alkyl, haloCi.6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi-6alkyl, Cι-6alkoxyCi.6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-6alkyl)aminoCi.6alkyl, bis(C1-6alkyl)aminoCi- 6alkyl, cyanoCi-6alkyl, Ci.6alkylsulfonyl, Ci-6alkanoylamino, Ci-6alkanoyl(Ci- 6alkyl)amino, carbamoyl, Ci-ealkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R13, R14, R15, R16 and R18 are independently hydrogen or a group selected from Ci.6alkyl, carbocyclyl, carbocyclylCi_6alkyl, heterocyclyl and heterocyclylCi-ealkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-ealkyl, Ci-6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, C].6alkoxyCi-6alkyl, Ci-6alkoxyCi.6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci.6alkyl)aminoCi-6alkyl, bis(Ci-6alkyl)aminoCi- 6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci.<;alkylsulfonylamino, Ci-6alkylsulfonyl(Ci- 6alkyl)amino, sulfamoyl, Ci-ealkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci.6alkanoyl(Ci.6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl for use as a medicament in the treatment of proliferative disease.
In accordance with another aspect of the present invention, there is provided a compound of formula (I)
Figure imgf000015_0001
formula (I) or a pharmaceutically acceptable salt thereof; wherein m is O, 1, 2, 3 or 4;
1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is
CR8;
X is a linker group selected from -CR4=CR5-, -CR4=CR5CR6R7-, -CR6R7CR5=CR4-, -C≡C-, -C≡CCR6R7-, -CR6R7C≡C-, -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-,
-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)NR5CR6R7-, -S(O)2NR4CR6R7-, -C(O)NR4-,
-NR4C(O)-, -NR4C(O)NR5-, -S(O)2NR4- and -NR4S(O)2-;
R1 is a'group selected from Ci-6alkyl, C2-6alkenyl, Ca-όalkynyl, carbocyclyl, carbocyclylCi.
6alkyl, heterocyclyl and heterocyclylCi-6alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R9, -OR9, -SR9, -SOR9, -
SO2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2R10, -
NR9CONR10R15, -NR9COCONR10R15 and -NR9SO2R10; or X-R1 is -CR6R7OH;
R2 is a group selected from Ci-6alkyl, carbocyclyl and heterocyclyl which group is substituted by -NR17SO2R18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -SR11, -SOR11, -SO2R1 1,
-COR1 1, -CO2R11, -CONR1 1R12, -NR1 1R12, -NR1 1COR12, and -NR11COCONR12R16; each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -SR13, -SOR13, -SO2R13, -COR13, -CO2R13, -CONR13R14, -NR13R14, -NR13COR14, -NR13CO2R14 and -NR13SO2R14; R and R5 are independently hydrogen or Ci-6alkyl; or R1 and R4 together with the atom or atoms to which they are attached form a 5- to 10- membered carbocyclic or heterocyclic ring wherein 1 , 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, Ci^alkoxy, haloCj. 6alkyl, haloCi-όalkoxy, hydroxyCi-6alkyl, hydroxyCi-ealkoxy, Ci-6alkoxyCi-6alkyl, Ci- 6alkoxyCi-6alkoxy, amino,
Figure imgf000016_0001
bis(Ci-6alkyl)amino, aminoC1-6alkyl, (Ci- 6alkyl)aminoCi-6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, d-galkylsulfonyl, Ci- 6alkylsulfonylamino, Ci.oalkylsulfonyl(Ci-6alkyl)amino, sulfamoyl, Ci^alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, C1-ϋalkanoylamino,
Figure imgf000016_0002
carbamoyl, Ci- 6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R6 and R7 are independently selected from hydrogen, halo, cyano, nitro and Ci-6alkyl; R8 is selected from hydrogen, halo, cyano and C1-6alkyl;
R9 and R10 are independently hydrogen or a group selected from Ci^alkyl, carbocyclyl, carbocyclylCi-ealkyl, heterocyclyl and
Figure imgf000016_0003
which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-ealkyl, Ci-ealkoxy, haloCi_6alkyl, haloCi-6alkoxy, hydroxyC1-6alkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi-6alkyl, d-6alkoxyCi.6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-βalkyl, (Ci-ealky^aminoCi-ealkyl, bis(Ci-6alkyl)aminoC1-6alkyl, cyanoCi-6alkyl, Ci-Oalkylsulfonyl, Ci-ealkylsulfonylamino, Ci-6alkylsulfonyl(Ci.6alkyl)amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfanioyl, Ci-6alkanoylamino, Ci^alkanoy^C^ 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R11, R12 and R17 are independently hydrogen or a group selected from Ci-6alkyl, carbocyclyl, carbocyclylCi-6alkyl, heterocyclyl and heteiOcyclylCi-6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C] -6alkyl, Ci-6alkoxy, haloCi_6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-βalkoxy, Ci-6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-όalkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci.6alkyl)aminoCi-6alkyl, bis^i-όalky^aminoCi. 6alkyl,
Figure imgf000017_0001
Ci-6alkanoylamino, Ci-6alkanoyl(Ci.
6alkyl)amino, carbamoyl, Ci-Oalkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R13, R14, R15, R16 and R18 are independently hydrogen or a group selected from Ci.6alkyl, carbocyclyl, carbocyclylCi-6alkyl, heterocyclyl and heterocyclylCi-oalkyl which group is 5 optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-όalkyl, Ci-5alkoxy,
Figure imgf000017_0002
haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-βalkoxy, Ci-βalkoxyCi-oalkyl, Ci-6alkoxyCi.6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi.0alkyl,
Figure imgf000017_0003
bis(Ci-6alkyl)aniinoCi.
6alkyl, cyanoCi-όalkyl, C[.6alkylsulfonyl, Ci-όalkylsulfonylamino, Ci-6alkylsulfonyl(Ci. io 6alkyl)amino, sulfanioyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci.6alkanoylamino,
Ci-balkanoyl(Ci-6alkyl)amino, carbamoyl, Ci.6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl for use as a medicament in the treatment of proliferative disease.
In accordance with another aspect of the present invention, there is provided the use of a compound of formula (I)
Figure imgf000017_0004
formula (I) or a pharmaceutically acceptable salt thereof; wherein m is O, 1, 2, 3 or 4; 1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is
20 CR8;
X is a linker group selected from -CR4=CR5-, -CR4=CR5CR6R7-, -CR6R7CR5^CR4-, -C≡C-, -CH=CCR6R7-, -CR6R7C=C-, -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR0R7-, -S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR0R7-, -NR4S(O)2CR6R7-, -S(O)2NR4CR6R7-, -C(O)NR4-, -NR4C(O)-, -NR4C(O)NR5-,
2s -S(O)2NR4- and -NR4S(O)2-;
R1 is a group selected from hydrogen, Ci.6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, carbocyclylCi-6alkyl, heterocyclyl and heterocyclylCi-όalkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, -R9, -OR9, -SR9, -SOR9, -SO2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2R10, -NR9CONR10R15, -NR9COCONR10R15 and -NR9SO2R10; R2 is a group selected from C^alkyl, carbocyclyl and heterocyclyl which group is substituted by -NR17SO2R18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, - SR11, -SOR11, -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR11R1^ -NR11COR12, and -NR11COCONR12R16; each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -SR13, -SOR13, -SO2R13, -COR13, -CO2R13, -CONR13R14, -NR13R14, -NR13COR14, -NR13CO2R14 and -NR13SO2R14;
R4 and R3 are independently hydrogen or
Figure imgf000018_0001
or R1 and R4 together with the atom or atoms to which they are attached form a 5- to 10- membered carbocyclic or heterocyclic ring wherein 1 , 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, Ci-6alkoxy, haloCi- 6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi-6alkyl, C1. όalkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi_6alkyl, (C1- όalkyDaminoCi-ealkyl, bis(Ci.6alkyl)aminoCi-6alkyl, cyanoCi-βalkyl, Ci_6alkylsulfonyl, C1- δalkylsulfonylamino, Ci-6alkylsulfonyl(Ci.6alkyl)amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci.6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000018_0002
carbamoyl, C1- δalkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R6 and R7 are independently selected from hydrogen, halo, cyano, nitro and Ci^alkyl; R8 is selected from hydrogen, halo, cyano and Ci^alkyl; R9 and R10 are independently hydrogen or a group selected from Ci-6alkyl, carbocyclyl, carbocyclylC1-6alkyl, heterocyclyl and heterocyclylCi^alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-βalkyl, Ci-6alkoxy, haloCi_6alkyl, haloCi-0alkoxy, hydroxyCi-όalkyl, hydroxyCi-6alkoxy, Ci-όalkoxyCi-6alkyl,
Figure imgf000018_0003
amino, Ci.δalkylamino, bis(Cι-6alkyl)amino, aminoCi.6alkyl, (Ci-6alkyl)aminoCi-6alkyl, bis(Ci.6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-ealkylsulfonyl, Ci-6alkylsulfonylamino, C|.όalkylsulfonyl(Ci-6alkyl)amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci.6alkanoylamino, Ci-6alkanoyl(Ci. 6alkyl)amino, carbamoyl, Ci.6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R11, R12 and R17 are independently hydrogen or a group selected from Ci-ealkyl, carbocyclyl, carbocyclylCi-6alkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, Ci-6alkoxy, haloCi-βalkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-ealkoxy, Ci-6alkoxyCi-6alkyl,
Figure imgf000019_0001
amino, Ci-6alkylamino, bis(Ci.6alkyl)amino, aminoC1-6alkyl, (Ci.6alkyl)aminoCi-6alkyl, bis^i-δalky^aminoC!. όalkyl, cyanoCi-όalkyl, Ci-ealkylsulfonyl, Ci-6alkanoylamino, Ci-6alkanoyl(Ci. όalkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R13, R14, R15, R16 and R18 are independently hydrogen or a group selected from C].6alkyl, carbocyclyl, carbocyclylCi^alkyl, heterocyclyl and heterocyclylCi-6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci^alkyl, Ci-(;alkoxy, haloCi-ealkyl, haloCi-6alkoxy, hydroxyC^alkyl, hydroxyCi-eallcoxy, Ci.ealkoxyCi-ealkyl, Ci-6alkoxyC1-6alkoxy, amino, Ci-ealkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl,
Figure imgf000019_0002
Ms(Ci -6alkyl)aminoCi. ealkyl, cyanoCi-6alkyl, Cj-όalkylsulfonyl, Ci-6alkylsulfonylamino, Ci.6alkylsulfonyl(Ci. ealkyl)amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-ealkanoylamino, C|.6alkanoyl(Ci-6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and Ms(Ci- 6alkyl)carbamoyl, in the manufacture of a medicament for use in the treatment of proliferative disease. In accordance with another aspect of the present invention, there is provided the use of a compound of formula (I)
Figure imgf000019_0003
formula (I) or a pharmaceutically acceptable salt thereof; wherein m is 0, 1, 2, 3 or 4;
1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is CR8; X is a linker group selected from -CR4=CR5-, -CR4^CR5CR6R7-, -CR6R7CR5=CR4-, -C=C-, -C=CCR6R7-, -CR6R7C=C-, -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-, -S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7-, -NR4S(O)2CR6R7-, -S(O)2NR4CR6R7-, -C(O)NR4-, -NR4C(O)-, -NR4C(O)NR5-, -S(O)2NR4- and -NR4S(O)2-;
R1 is a group selected from d-ealkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, carbocyclylCi. 6alkyl, heterocyclyl and heterocyclylCi-oalkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, -R9, -OR9, -SR9, -SOR9, -SO2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2R10, o -NR9CONR10R15, -NR9COCONR10R15 and -NR9SO2R10; or X-R1 is -CR6R7OH;
R2 is a group selected from Ci^alkyl, carbocyclyl and heterocyclyl which group is substituted by -NR17SO2R18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, - SR11, -SOR11, -SO2R11,s -COR11, -CO2R11, -CONR11R12, -NR11R12, -NR11COR12, and -NR11COCONR12R16; each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -SR13, -SOR13, -SO2R13, -COR13, -CO2R13, -CONR13R14, -NR13R14, -NR13COR14, -NR13CO2R14 and -NR13SO2R14; R4 and Rs are independently hydrogen or Ci-6alkyl; Q or R1 and R4 together with the atom or atoms to which they are attached form a 5- to 10- membered carbocyclic or heterocyclic ring wherein 1 , 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, Ci-6alkoxy, haloC^ 6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Cj.(,alkoxyCi-6alkyl, C1.5 6alkoxyC1-6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci- 6alkyl)aminoCi-όalkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi^alkyl, Ci-6alkylsulfonyl, Ci- 6alkylsulfonylamino, Ci.6alkylsulfonyl(Ci-6alkyl)amino, sulfamoyl, C1-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci-6alkanoyl(Ci_6alkyl)amino, carbamoyl, Ci- 6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; 0 R6 and R7 are independently selected from hydrogen, halo, cyano, nitro and Ci-6alkyl; R8 is selected from hydrogen, halo, cyano and Ci-βalkyl; R9 and R10 are independently hydrogen or a group selected from Ci-6alkyl, carbocyclyl, carbocyclylCi-0alkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-ealkyl, Ci-6alkoxy, haloCi.6alkyl, haloCi-ealkoxy, hydroxyCi.0alkyl,
Figure imgf000021_0001
Ci-0alkoxyC1-ealkyl, Ci-6alkoxyCi.6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ϋalkyl)aminoCι-6alkyl, bis(Ci.6alkyl)aminoCi-6alkyl,
Figure imgf000021_0002
Ci-6alkylsulfonyl, Ci.0alkylsulfonylamino, Ci-όalkylsulfony^Ci-oalky^amino, sulfamoyl, C^alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-ealkanoylamino, Ci.6alkanoyl(Ci. t,alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R11, R12 and R17 are independently hydrogen or a group selected from Ci^alkyl, carbocyclyl, carbocyclylCi-6alkyl, heterocyclyl and
Figure imgf000021_0003
which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-Oalkyl, Ci-Oalkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi^alkyl, hydroxyCi_6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci^alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-balkyl)aminoCi-6alkyl, bis(Ci.6alkyl)aminoCi. δalkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-balkanoylamino, Ci-6alkanoyl(Ci. 6alkyl)amino, carbamoyl, Cι.6alkylcarbamoyl and bis(Ci-0alkyl)carbamoyl; R13, R14, R15, Rlb and R18 are independently hydrogen or a group selected from Ci-t,alkyl, carbocyclyl, carbocyclylCi-t,alkyl, heterocyclyl and heteiOcyclylCi_balkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-ealkyl, Ci-6alkoxy, haloCi-balkyl, haloCι-6alkoxy,
Figure imgf000021_0004
hydroxyCi-6alkoxy, Ci-όalkoxyCi-βalkyl, Ci-6alkoxyCi_6alkoxy, amino, Ci-6alkylamino, bis(Ci.6alkyl)amino, aminoCi.(,alkyl, (Ci-6alkyl)aminoCi-6alkyl, bis(Ci-6alkyl)aminoC1- oalkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino,
Figure imgf000021_0005
6alkyl)amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci-6alkanoyl(Ci-6alkyl)amino, carbamoyl,
Figure imgf000021_0006
and bis(Ci-balkyl)carbamoyl in the manufacture of a medicament for use in the treatment of proliferative disease.
In accordance with another aspect of the present invention, there is provided the use of a compound of formula (I)
Figure imgf000022_0001
formula (I) or a pharmaceutically acceptable salt; wherein m is O, 1, 2, 3 or 4; 1Y and Y2 are independently N or CR8 provided that one of Y and Y2 is N and the other is CR8;
X is a linker group selected from -CR4=CR5-, -CR^CR5CR6R7-, -CR6R7CR5^CR4-, -C=C-, -C=CCR6R7-, -CR0R7C=C-, -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR0R7-, -S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)NR5CR6R7-, -S(O)2NR4CR6R7-, -C(O)NR4-, -NR4C(O)-, -NR4C(O)NR5-, -S(O)2NR4- and -NR4S(O)2-;
R1 is a group selected from Ci-6alkyl, C2.6alkenyl, C2-balkynyl, carbocyclyl, carbocyclylCi. balkyl, heterocyclyl and heterocyclylCi-oalkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, -R9, -OR9, -SR9, -SOR9, -SO2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2R10, -NR9CONR10R15, -NR0COCONR10R15 and -NR9SO2R10; or X-R1 is -CR6R7OH
R2 is a group selected from Ci-βalkyl, carbocyclyl and heterocyclyl which group is substituted by -NR17SO2R18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, - SR1 1, -SOR11, -SO2R11, -COR11, -CO2R1 1, -CONR11R12, -NR11R12, -NR11COR12, and -NR1 1COCONR12R16; each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -SR13, -SOR13, -SO2R13, -COR13, -CO2R13, -CONR13R14, -NR13R14, -NR13COR14, -R13CO2R14 and -NR13SO2R14; R4 and R5 are independently hydrogen or Ci-6alkyl; or R and R4 together with the atom or atoms to which they are attached form a 5- to 10- membered carbocyclic or heterocyclic ring wherein 1 , 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more -Y>-
substituent groups selected from halo, cyano, nitro, hydroxy,
Figure imgf000023_0001
Ci.ealkoxy, haloCi- 6alkyl, haloCi-6alkoxy,
Figure imgf000023_0002
Ci- 6alkoxyCi-6alkoxy, amino, Ci-6alkylamiiio5 bis(Ci-6alkyl)aniino, aminoCi-όalkyl, (Ci- 6alkyl)aminoCi-6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci- 6alkylsulfonylamino, Ci-6alkylsulfonyl(Ci.6alkyl)amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci-6alkanoyl(Ci-6alkyl)amino, carbamoyl, Ci- όalkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R6 and R7 are independently selected from hydrogen, halo, cyano, nitro and C[.6alkyl; R8 is selected from hydrogen, halo, cyano and Ci^alkyl; R9 and R10 are independently hydrogen or a group selected from C[.6alkyl, carbocyclyl, carbocyclylCi-όalkyl, heterocyclyl and
Figure imgf000023_0003
which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, Ci-6alkoxy, haloCi^alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyC^alkoxy, Cj-ealkoxyCuόalkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino,
Figure imgf000023_0004
(Ci-όalkyDaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000023_0005
Ci-όalkylsulfonyl, Ci-ealkylsulfonylamino, Ci.6alkylsulfonyl(C1-6alkyl)amino, sulfamoyl, Ci^alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci-όalkanoy^Ci. 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R11, R12 and R17 are independently hydrogen or a group selected from Ci-6alkyl, carbocyclyl, carbocyclylC1-6alkyl, heterocyclyl and heterocyclylCi-ealkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, Ci-6alkoxy,
Figure imgf000023_0006
haloCi-βalkoxy, hydroxyCi-6alkyl, hydroxyCuδalkoxy, Ci-βalkoxyCi-όalkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(C1-6alkyl)amino, aminoCi-6alkyl, (Ci-6alkyl)aminoCι-6alkyl, bis(Ci.6alkyl)aminoCi. 6alkyl, cyanoCi_6alkyl, Ci-ealkylsulfonyl, Ci-6alkanoylamino, Ci-ealkanoylCC!. 6alkyl)amino, carbamoyl, Ci^alkylcarbamoyl and bis(Ci.6alkyl)carbamoyl; R13, R14, R15, R16 and R18 are independently hydrogen or a group selected from Ci.6alkyl, carbocyclyl, carbocyclylCi-6alkyl, heterocyclyl and heterocyclylCi-6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, Ci_6alkoxy, haloCi.6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyC|.6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-6alkoxyCi.6alkoxy, amino, C1-6alkylamino, bis(Ci.6alkyl)amino, aminoCi-6alkyl, (Ci-6alkyl)aminoCi.6alkyl, bis(Ci-6alkyl)aminoCi. βalkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-ealkylsulfonylamino, Ci-6alkylsulfonyl(Cι. 6alkyl)amino, sulfamoyl, Ci.6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci.6alkanoylamino, Ci-6alkanoyl(Ci_6alkyl)amino, carbamoyl, Ci_6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl in the manufacture of a medicament for use in the treatment of proliferative disease.
In accordance with a further aspect of the present invention, there is also provided a compound of formula (I)
Figure imgf000024_0001
formula (I) or a pharmaceutically acceptable salt thereof; wherein m is 0, 1, 2, 3 or 4;
1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is
CR8;
X is a linker group selected from -CR4=CR5-, -CR4=CR5CR6R7-, -CR6R7CR5=CR4-,
-C≡C-, -C≡CCR6R7-, -CR6R7C≡C-, -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-, -S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7-,
-NR4S(O)2CR6R7-, -S(O)2NR4CR6R7-, -C(O)NR4-, -NR4C(O)-, -NR4C(O)NR5-, -(O)2NR4- and -NR4S(O)2-;
R1 is a group selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, carbocyclylQ.όalkyl, heterocyclyl and
Figure imgf000024_0002
which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, -R' , -OR' ,
-SR9, -SOR9, -O2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2R10,
-NR9CONR10R15, -NR9COCONR10R15 and NR9SO2R10;
R2 is a group selected from Ci-6alkyl, carbocyclyl and heterocyclyl which group is substituted by -NR17SO2R18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR1 1, -SR1 1, -SOR1 1, -SO2R11,
-COR11, -CO2R1 1, -CONR11R12, -NR11R12, -NR1 1COR12, and -NR11COCONR12R16; each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -R13, -SOR13, -SO2R13, -COR13, -CO2R13, -CONR13R14, -NR13R14, -NR13COR14, - NR13CO2R14 and -NR13SO2R14; R4 and R5 are independently hydrogen or Ci.6alkyl; or R1 and R4 together with the atom or atoms to which they are attached form a 5- to 10- membered carbocyclic or heterocyclic ring wherein 1 , 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-ealkyl, Ci-6alkoxy, haloCi. όalkyl, haloCi-6alkoxy, hydroxyCi-βalkyl, hydroxyCi-6alkoxy, Ci-ealkoxyCi-ealkyl, Ci- 6alkoxyCi-6alkoxy, amino, Cusalkylamino, bis(Ci-6alkyl)amino, aminoCi-βalkyl, (Ci- 6alkyl)aminoCi-6alkyl, bis(Ci-6alkyl)aminoCi-balkyl, cyanoCi-όalkyl, Ci-6alkylsulfonyl, Ci- Oalkylsulfonylamino, Ci.6alkylsulfonyl(Ci-0alkyl)amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000025_0001
carbamoyl, Ci- 6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R6 and R7 are independently selected from hydrogen, halo, cyano, nitro and C^aHcyl; R8 is selected from hydrogen, halo, cyano and Ci-6alkyl;
R9 and R10 are independently hydrogen or a group selected from
Figure imgf000025_0002
carbocyclyl, carbocyclylCi-6alkyl, heterocyclyl and heteiOcyclylC1-6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-ealkyl, Ci-6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi_6alkyl, hydroxyCi-βalkoxy, Ci-6alkoxyCi_6alkyl, 0!-63IkOXyCi-OaIkOXy, amino, Ci-ealkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci.6alkyl)aminoCi-6alkyl, bis(C].6alkyl)aminoCi-6alkyl,
Figure imgf000025_0003
Ci-όalkylsulfonyl, Ci-6alkylsulfonylamino, Ci.6alkylsulfonyl(Ci-balkyl)amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfanioyl, C1-6alkanoylamino, Ci.6alkanoyl(Ci. 6alkyl)amino, carbamoyl, C].6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R11, R12 and R17 are independently hydrogen or a group selected from Ci-6alkyl, carbocyclyl, carbocyclylCi.6alkyl, heterocyclyl and heterocyclylCi-6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, Ci-6alkoxy, haloCi.6alkyl, haloCi-6alkoxy, hydroxyCu6alkyl, hydroxyCi-balkoxy, Ci-6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyDaminoCi-όalkyl, bis(Ci-6alkyl)aminoCi_ 6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-ealkanoylamino, Ci-6alkanoyl(Ci.
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R13, R14, R15, R16 and R18 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi-όalkyl, heterocyclyl and heterocyclylCi-6alkyl which group is 5 optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-όalkyl, Ci-6alkoxy, haloCi-6alkyl, haloCi.δalkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci_6alkoxyCi-6alkyl, Ci-δalkoxyCi-όalkoxy, amino, Ci-όalkylamino, bis(C1.6alkyl)amino, aminoCi-6alkyl, (Ci.6alkyl)aminoCi-6alkyl, bis(Ci.6alkyl)aminoCi.
6alkyl, cyanoCi.6alkyl, Ci^alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-6alkylsulfonyl(Ci. io 6alkyl)amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci_6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000026_0001
carbamoyl, Ci-galkylcarbamoyl and Ms(Ci- 6alkyl)carbamoyl.
In accordance with a further aspect of the present invention, there is also provided a compound of formula (I)
Figure imgf000026_0002
formula (I) or a pharmaceutically acceptable salt thereof; wherein m is O, 1, 2, 3 or 4; 1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is
20 CR8;
X is a linker group selected from -CR4=CR5-, -CR4=CR5CR6R7-, -CR6R7CR5=CR4-, -C≡C-, -C≡CCR6R7-, -CR6R7C≡C-, -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-, -S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7-, -NR4S(O)2CR6R7-, -S(O)2NR4CR6R7-, -C(O)NR4-, -NR4C(O)-, -NR4C(O)NR5-, -(O)2NR4-
25 and -NR4S(O)2-;
R1 is a group selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, carbocyclylCi. βalkyl, heterocyclyl and heterocyclylCi-balkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, -R9, -OR9, -SR9, -SOR9,
-O2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2R10, -
NR9CONR10R15, -NR9COCONR10R15 and NR9SO2R10; or X-R1 is -CR6R7OH; R2 is a group selected from C^aHcyl, carbocyclyl and heterocyclyl which group is substituted by -NR17SO2R18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -SR11, -SOR11, -SO2R1 1,
-COR11, -CO2R11, -CONR11R12, -NR1 1R12, -NR11COR12, and -NR1 1COCONR12R16; each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -R13, "SOR13, -SO2R13, -COR13, -CO2R13, -CONR13R14, -NR13R14, -NR13COR14, -
NR13CO2R14 and -NR13SO2R14;
R4 and R5 are independently hydrogen or Ci.όalkyi; or R1 and R4 together with the atom or atoms to which they are attached form a 5- to 10- membered carbocyclic or heterocyclic ring wherein 1 , 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-ealkyl, Ci-ealkoxy, haloCi.
6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-ealkoxy,
Figure imgf000027_0001
Ci-
6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi_6alkyl, (Ci.
6alkyl)aminoC1-6alkyl, bis(Ci-6alkyl)aniinoCi.6alkyl, cyanoCi-6alkyl, Ci-ealkylsulfonyl, Ci- ealkylsulfonylamino, Ci-6alkylsulfonyl(Ci-6alkyl)amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci.6alkanoylamino, Ci-6alkanoyl(Ci-6alkyl)amino, carbamoyl, Ci- όalkylcarbamoyl and bis(Ci_6alkyl)carbamoyl;
R6 and R7 are independently selected from hydrogen, halo, cyano, nitro and Ci-6alkyl;
R8 is selected from hydrogen, halo, cyano and Ci-6alkyl; R9 and R10 are independently hydrogen or a group selected from Ci-6alkyl, carbocyclyl, carbocyclylC].6alkyl, heterocyclyl and heterocyclic i-6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy,
Ci-6alkyl, Ci-6alkoxy,
Figure imgf000027_0002
haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy,
Ci_6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-ealkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-6alkyl)aminoCi.6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl,
C i-6alkylsulfonyl, C i^alkylsulfonylamino, Ci-6alkylsulfonyl(C i-6alkyl)amino, sulfamoyl, Ci.6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci_6alkanoylamino, Ci-6alkanoyl(Ci. 6alkyl)amino, carbamoyl, Ci-ύalkylcarbamoyl and bis(Ci_6alkyl)carbamoyl; R11, R12 and R17 are independently hydrogen or a group selected from Chalky., carbocyclyl, carbocyclylCi.6alkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, Ci-6alkoxy,
Figure imgf000028_0001
haloCi-6alkoxy, hydroxyCι-6alkyl, hydroxy C i_6alkoxy, Ci-όalkoxyCi-βalkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-ealkylamino, bis(Ci.6alkyl)amino, aminoCi-6alkyl,
Figure imgf000028_0002
bis(Ci.6alkyl)aminoCi- 6alkyl, cyanoCi-6alkyl, Ci_6alkylsulfonyl, Ci-6alkanoylamino, Ci-6alkanoyl(Ci. 6alkyl)amino, carbamoyl, Ci-ealkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R13, R14, R15, R16 and R18 are independently hydrogen or a group selected from
Figure imgf000028_0003
carbocyclyl,
Figure imgf000028_0004
which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, C1-6alkoxy,
Figure imgf000028_0005
haloC1-6alkoxy, hydroxyCi-ealkyl, hydroxyCi-6alkoxy,
Figure imgf000028_0006
Ci-6alkoxyCi-(,alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-6alkyl)aminoCi-όalkyl, bis(Ci-6alkyl)aminoCi. 6alkyl, cyanoCi-6alkyl, Ci.6alkylsulfonyl, Ci-όalkylsulfonylamino, Ci.6alkylsulfonyl(d. 6alkyl)amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(C1-6alkyl)sulfamoyl, Ci-όalkanoylamino, Ci-6alkanoyl(Ci.6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and Ws(Ci- 6alkyl)carbamoyl.
In accordance with a further aspect of the present invention, there is also provided a compound of formula (I)
Figure imgf000028_0007
formula (I) or a pharmaceutically acceptable salt thereof; wherein m is 0, 1, 2, 3 or 4; 1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is
CR8;
X is a linker group selected from -CR4=CR5-, -CR4=CR5CR6R7-, -CR6R7CR5=CR4-,
-C≡C-, -C≡CCR6R7-, -CR6R7C=C-, -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-, s -S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)NR5CR6R7-, -S(O)2NR4CR6R7-, -C(O)NR4-, -NR4C(O)-, -NR4C(O)NR5-, -S(O)2NR4- and -NR4S(O)2-;
R1 is a group selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, carbocyclylC]. 6alkyl, heterocyclyl and heterocyclylCi-6alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, -R9, -OR9, -SR9, -SOR9,o -O2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2R10, - NR9CONR10R15, -NR9COCONR10R15 and NR9SO2R10; or X-R1 is -CR6R7OH;
R2 is a group selected from Ci-6alkyl, carbocyclyl and heterocyclyl which group is substituted by -NR17SO2R18 and optionally substituted by one or more substituent groups independently selected from halo, cyano, nitro, -R11, -OR11, -SR11, -SOR11, -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR11R12, -NR11COR12, and -NR11COCONR12R16; each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -R13, "SOR13, -SO2R13, -COR13, -CO2R13, -CONR13R14, -NR13R14, -NR13COR14, - NR13CO2R14 and -NR13SO2R14; 0 R4 and R5 are independently hydrogen or Ci-6alkyl; or R1 and R4 together with the atom or atoms to which they are attached form a 5- to 10- membered carbocycHc or heterocyclic ring wherein 1 , 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy,
Figure imgf000029_0001
C1-6alkoxy, haloCi.s 6alkyl, haloCi.6alkoxy, hydroxyC1-6alkyl, hydiOxyCi-βalkoxy, C1-6alkoxyCi-6alkyl, Ci- (,alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci- 6alkyl)aminoCi.6alkyl, bis(Ci-6alkyl)aminoCi.6alkyl, cyanoCi-δalkyl, C|_6alkylsulfonyl, Ci- 6alkylsulfonylamino, Ci-6alkylsulfonyl(Ci-6alkyl)amino, sulfamoyl, Ci-βalkylsulfamoyl, bis(C]-6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci.6alkanoyl(Ci-6alkyl)amino, carbamoyl, Ci-0 6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R6 and R7 are independently selected from hydrogen, halo, cyano, nitro and Ci-6alkyl; R8 is selected from hydrogen, halo, cyano and Ci.6alkyl; R9 and R10 are independently hydrogen or a group selected from Ci-6alkyl, carbocyclyl, carbocyclylCi.galkyl, heterocyclyl and heterocyclylCi-galkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-βalkyl, Ci-ealkoxy, haloCi-6alkyl, haloCi.galkoxy, hydroxyCi-όalkyl, hydroxyCi-6alkoxy, Ci-όalkoxyCi-ealkyl, Ci.6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi_6alkyl, (Ci-6alkyl)aminoCi-6alkyl, bis(Ci-6alkyl)aminoCi.6alkyl, cyanoCi-όalkyl, Ci-6alkylsulfonyl, C[.6alkylsulfonylamino, Ci.6alkylsulfonyl(Ci-6alkyl)amino, sulfamoyl, Ci_6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyls Ci^alkanoylamino, Ci-6alkanoyl(Ci. 6alkyl)amino, carbamoyl, Ci.6alkylcarbamoyl and bis(C[.6alkyl)carbamoyl; R11, R12 and R17 are independently hydrogen or a group selected from Ci.6alkyl, carbocyclyl, carbocyclylCi-ealkyl, heterocyclyl and heterocyclylCi-oalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy,
Figure imgf000030_0001
hydroxyCi.6alkyl, hydroxyCi-ealkoxy, Ci-όalkoxyCi-όalkyl,
Figure imgf000030_0002
amino, Ci-6alkylamino, bis(Ci.όalkyl)amino, aminoCi-6alkyl, (Ci..6alkyl)aminoCi.6alkyl, bis(Ci-6alkyl)aminoCi- 6alkyl, cyanoCi_6alkyl, Ci-βalkylsulfonyl,
Figure imgf000030_0003
Ci.6alkanoyl(Ci. 6alkyl)amino, carbamoyl,
Figure imgf000030_0004
and bis(Ci-6alkyl)carbamoyl; R13, R14, R1S, R16 and R18 are independently hydrogen or a group selected from
Figure imgf000030_0005
carbocyclyl, carbocyclylCi-όalkyl, heterocyclyl and heterocyclylCi^alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, C1-6alkoxy, haloCi-6alkyl, haloC1-6alkoxy, hydroxy C i^alkyl, hydroxyCi.6alkoxy, Ci_6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-ealkylamino, bis(Ci-6alkyl)amino, aminoCi.galkyl, (Ci-6alkyl)aminoCi-6alkyl, bis(C1-6alkyl)aminoC|_ 6alkyl, cyanoCi-6alkyl, d-όalkylsulfonyl, Ci-6alkylsulfonylamino,
Figure imgf000030_0006
6alkyl)amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci-6alkanoyl(Ci.6alkyI)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(C1. 6alkyl)carbamoyl.
Certain compounds of formula (I) are capable of existing in stereoisomer^ forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention. Solvates and mixtures thereof also form an aspect of the present invention. For example, a suitable solvate of a compound of formula (I) is, for example, a hydrate such as a hemi-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate or an alternative quantity thereof.
The present invention relates to the compounds of formula (I) as herein defined as well as to salts thereof. Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula (I) and their pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the invention may, for example, include acid addition salts of compounds of formula (I) as herein defined which are sufficiently basic to form such salts. Such acid addition salts include but are not limited to furmarate, methanesulfonate, hydrochloride, hydrobromide, citrate and maleate salts and salts formed with phosphoric and sulfuric acid. In addition where compounds of formula (I) are sufficiently acidic, salts are base salts and examples include but are not limited to, an alkali metal salt for example sodium or potassium, an alkaline earth metal salt for example calcium or magnesium, or organic amine salt for example triethylamine, ethanolamine, diethanolamine, triethanolamine, morpholine, iV-methylpiperidine, iV-ethylpiperidine, dibenzylamine or amino acids such as lysine.
The compounds of formula (I) may also be provided as in vivo hydrolysable esters. An in vivo hydrolysable ester of a compound of formula (I) containing carboxy or hydroxy group is, for example a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid or alcohol. Such esters can be identified by administering, for example, intravenously to a test animal, the compound under test and subsequently examining the test animal's body fluid.
Suitable pharmaceutically acceptable esters for carboxy include Ci-6alkoxymethyl esters for example methoxymethyl, Ci-όalkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C3-8cycloalkoxycarbonyloxyCi.6alkyl esters for example 1-cyclohexylcarbonyloxy ethyl, l,3-dioxolen-2-onylmethyl esters for example 5-methyl-l,3-dioxolen-2-onylmethyl, and Ci-6alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl; and may be formed at any carboxy group in the compounds of this invention. Suitable pharmaceutically acceptable esters for hydroxy include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and α-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxyniethoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include Ci-[0alkanoyl, for example formyl, acetyl, benzoyl, phenylacetyl, substituted benzoyl and phenylacetyl; Ci-i0alkoxycarbonyl (to give alkyl carbonate esters), for example ethoxycarbonyl; di-Ci-4alkylcarbamoyl and λ^di-C^alkylaminoethy I)-N-C i-4alkylcarbamoyl (to give carbamates); di-C(- 4alkylaminoacetyl and carboxy acetyl. Examples of ring substituents on phenylacetyl and benzoyl include aminomethyl, Ci-4alkylaminomethyl and di-(Ci-4alkyl)aminomethyl, and morpholino or piperazino linked from a ring nitrogen atom via a methylene linking group to the 3- or 4- position of the benzoyl ring. Other interesting in vivo hydrolysable esters include, for example, RAC(O)OCi-6alkyl-CO-, wherein RΛ is for example, benzyloxy-Ci- 4alkyl, or phenyl. Suitable substituents on a phenyl group in such esters include, for example, 4-Ci-4piperazino-Ci-4alkyl, piperazino-Ci-4alkyl and morpholmo-Ci-4alkyl. The compounds of the formula (I) may be also be administered in the form of a prodrug which is broken down in the human or animal body to give a compound of the formula (I). Various forms of prodrugs are known in the art. For examples of such prodrug derivatives, see: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p. 113- 191 (1991); c) H. Bundgaard, Advanced Drug Deliver}' Reviews, 8, 1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).
In this specification the generic term "Cp.qalkyl" includes both straight-chain and branched-chain alkyl groups. However references to individual alkyl groups such as "propyl" are specific for the straight chain version only (i.e. /?-propyl and isopropyl) and references to individual branched-chain alkyl groups such as "tø/Y-butyl" are specific for the branched chain version only.
The prefix Cp-q in Cp-qalkyl and other terms (where p and q are integers) indicates the range of carbon atoms that are present in the group, for example Ci-4alkyl includes Cialkyl (methyl), C2alkyl (ethyl), C3alkyl (propyl as rc-propyl and isopropyl) and C4alkyl (n-butyl, sec-butyl, isobutyl and tert-hutyl).
The term Cp-qalkoxy comprises -O-Cp.qalkyl groups.
The term Cp-qalkanoyl comprises -C(O)alkyl groups. The term halo includes fluoro, chloro, bromo and iodo.
"Carbocyclyl" is a saturated, unsaturated or partially saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 14 ring atoms, wherein a ring CH2 group may be replaced with a C=O group. "Carbocyclyl" includes "aryl", "Cp- qCycloalkyl" and "Cp-qCycloalkenyl". "aryl" is an aromatic monocyclic, bicyclic or tricyclic carbcyclyl ring system.
"Cp-qcycloalkenyl" is an unsaturated or partially saturated monocyclic, bicyclic or tricyclic carbocyclyl ring system containing at least 1 C=C bond and wherein a ring CH2 group may be replaced with a C=O group.
"Cp-qcycloalkyl" is a saturated monocyclic, bicyclic or tricyclic carbocyclyl ring system and wherein a ring CH2 group may be replaced with a C=O group.
"Heterocyclyl" is a saturated, unsaturated or partially saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 14 ring atoms of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulfur or oxygen, which ring may be carbon or nitrogen linked and wherein a ring nitrogen or sulfur atom may be oxidised and wherein a ring CH2 group may be replaced with a C=O group. "Heterocyclyl" includes "heteroaryl", "cycloheteroalkyl" and "cycloheteroalkenyl".
"Heteroaryl" is an aromatic monocyclic, bicyclic or tricyclic heterocyclyl, particularly having 5 to 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulfur or oxygen where a ring nitrogen or sulfur may be oxidised. "Cycloheteroalkenyl" is an unsaturated or partially saturated monocyclic, bicyclic or tricyclic heterocyclyl ring system, particularly having 5 to 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulfur or oxygen, which ring may be carbon or nitrogen linked and wherein a ring nitrogen or sulfur atom may be oxidised and wherein a ring CH2 group may be replaced with a C=O group. "Cycloheteroalkyl" is a saturated monocyclic, bicyclic or tricyclic heterocyclic ring system, particularly having 5 to 10 ring atoms, of which 1 , 2, 3 or 4 ring atoms are chosen from nitrogen, sulfur or oxygen, which ring may be carbon or nitrogen linked and wherein a ring nitrogen or sulfur atom may be oxidised and wherein a ring CH2 group may be replaced with a C=O group.
This specification may make use of composite terms to describe groups comprising more than one functionality. Unless otherwise described herein, such terms are to be interpreted as is understood in the art. For example carbocyclylCp-qalkyl comprises Cp-qalkyl substituted by carbocyclyl, heteiOcyclylCp-qalkyl comprises Cp.qalkyl substituted by heterocyclyl, and bis(Cp-qalkyl)amino comprises amino substituted by 2 Cp- qalkyl groups which may be the same or different.
HaloCp-qalkyl is a Cp.qalkyl group that is substituted by 1 or more halo substituents and particuarly 1, 2 or 3 halo substituents. Similarly, other generic terms containing halo such as haloCp-qalkoxy may contain 1 or more halo substituents and particluarly 1 , 2 or 3 halo substituents.
HydroxyCp-qalkyl is a Cp-qalkyl group that is substituted by 1 or more hydroxy 1 substituents and particularly by 1 , 2 or 3 hydroxy substituents. Similarly other generic terms containing hydroxy such as hydroxy Cp-qalkoxy may contain 1 or more and particularly 1, 2 or 3 hydroxy substituents.
Cp.qalkoxyCp-qalkyl is a Cp-qalkyl group that is substituted by 1 or more Cp-qalkoxy substituents and particularly 1 , 2 or 3 Cp-qalkoxy substituents. Similarly other generic terms containing Cp.qalkoxy such as Cp-qalkoxyCP-qalkoxy may contain 1 or more Cp- qalkoxy substituents and particularly 1 , 2 or 3 Cp-qalkoxy substituents.
Where optional substituents are chosen from "1 or 2", from "1, 2, or 3" or from "1, 2, 3 or 4" groups or substituents it is to be understood that this definition includes all substituents being chosen from one of the specified groups i.e. all substitutents being the same or the substituents being chosen from two or more of the specified groups i.e. the substitutents not being the same.
Compounds of the present invention have been named with the aid of computer software (ACD/Name version 8.0).
"Proliferative disease(s)" includes malignant disease(s) such as cancer as well as non-malignant disease(s) such as inflammatory diseases, obstracutive airways diseases, immune diseases or cardiovascular diseases.
Suitable values for any R group or any part or substituted for such groups include: for methyl, ethyl, propyl, butyl, 2-methylpropyl and tert-butyl; or Ci-6alkyl: Cmalkyl, pentyl, 2,2-dimethylpropyl, 3-methylbutyl and hexyl; or C3.6cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; or C3-6Cy cloalkylCι-4alkyl: cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl; or aryl: phenyl and naphthyl; or arylCi-4alkyl: benzyl, phenethyl, naphthylmethyl and naphthylethyl; or carbocylyl: aiyl, cyclohexenyl and C^cycloalkyl; or halo: fluoro, chloro, bromo and iodo; or Ci.4alkoxy: methoxy, ethoxy, propoxy and isopropoxy; or Ci-6alkoxy: Ci^alkoxy, pentyloxy, 1-ethylpropoxy and hexyloxy; or Ci-ealkanoyl: acetyl, propanoyl and 2-methylpropanoyl; or heteroaryl: pyridyl, imidazolyl, quinolinyl, cinnolyl, pyrimidinyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, thiazolyl, triazolyl, oxazolyl, isoxazolyl, furanyl, pyridazinyl, pyrazinyl, indolyl, benzofuranyl, dibenzofuranyl and benzothienyl; or heteroarylCi-4alkyl: pyrrolylmethyl, pyiτolylethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, pyrazolylethyl, furanylmethyl, furanylethyl, thienylmethyl, theinylethyl, pyridylmethyl, pyridylethyl, pyrazinylmethyl, pyrazinylethyl, pyrimidinylmethyl, pyrimidinylethyl, pyrimidinylpropyl, pyrimidinylbutyl, imidazolylpropyl, imidazolylbutyl, quinolinylpropyl, 1,3,4-triazolylpropyl and oxazolylmethyl; for heterocyclyl: heteroaryl, pyiτolidinyl, isoquinolinyl, quinoxalinyl, benzothiazolyl, benzoxazolyl, piperidinyl, piperazinyl, azetidinyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, indolinyl, dihydro-2//-pyranyl and tetrahy dro furanyl . It should be noted that examples given for terms used in the description are not limiting. Particular values of m, X, 1Y and Y2, R1, R2 and R3 are as follows. Such values may be used where appropriate, in connect with any aspect of the invention, or part thereof, and with any of the definitions, claims or embodiments defined herein. m In one aspect of the invention m is 0, 1 , 2 or 3.
In another aspect m is 0, 1 or 2. In a further aspect m is 0 or 1. In yet another aspect m is 0 so that R is absent. In yet another aspect m is 1 and R3 is methyl. 1Y and Y2
In one aspect of the invention 1Y is N and Y2 is CR8. In another aspect 1Y is N and Y2 is CH. In yet another aspect 1Y is CR8 and Y2 is N. In a further aspect 1Y is CH or CF and Y2 is N. In yet a further aspect 1Y is CH and Y2 is N.
X
In one aspect of the invention X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-, -S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)NR5CR6R7-, -S(O)2NR4CR6R7-, -NR4C(O)-, -C(O)NR4-, -S(O)2NR4- and -NR4S(O)2-.
In another aspect X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-, -S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)NR5CR6R7-, -S(O)2NR4CR6R7, -C(O)NR4- and -NR4C(O)-.
In a further aspect X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-, -S(O)2CR6R7-, -C(O)NR4-, and -NR4C(O)-.
In a further aspect X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR0R7-, -S(O)CR6R7- and -S(O)2CR6R7-.
In yet another aspect X is a linker group selected from -SCR6R7-, -S(O)CR6R7- and -S(O)2CRbR7-. In another aspect X is a linker group selected from -NR4CH2-, -OCH2-,
-OCH(CH3)-, -OC(CHs)2-, -SCH2-, -SCH(CH3)-, -SC(CHs)2-, -S(O)CH2-, -S(O)CH(CH3)- , -S(O)C(CHs)2-, -S(O)2CH2-, -S(O)2CH(CH3)-, -S(O)2C(CHs)2-, -C(O)NR4- and -NR4C(O)-.
In another aspect X is a linker group selected from -NR4CH2-, -OCH2-, -SCH2-, -S(O)CH2-, -S(O)2CH2-, -C(O)NR4-, and -NR4C(O)-. In another aspect X is a linker group selected from -NR4CH2-, -OCH2-,
-OCH(CH3)-, -OC(CH3V, -SCH2-, -SCH(CH3)-, -SC(CH3);.-, -S(O)CH2-, -S(O)CH(CH3)- , -S(O)C(CHs)2-, -S(O)2CH2-, -S(O)2CH(CH3)- and -S(O)2C(CH3)2-.
In another aspect X is a linker group selected from -NR4CH2-, -OCH2-, -SCH2-, -S(O)CH2- and -S(O)2CH2-. In a further aspect X is a linker group selected from -NHCH2-, -N(CH3)CH2-,
-OCH2-, -OCH(CH3)-, -OC(CH3)2-5 -SCH2-, -SCH(CH3)-, -SC(CH3)2-, -S(O)CH2-, -S(O)CH(CH3)-, -S(O)C(CH3)2-, -S(O)2CH2-, -S(O)2CH(CH3)-, -S(O)2C(CHs)2-, -C(O)NH-, -C(O)N(CH3)-, -NHC(O)- and -N(CH3)C(O)-.
In a further aspect X is a linker group selected from -NHCH2-, -N(CH3)CH2-, -OCH2-, -SCH2-, -S(O)CH2-, -S(O)2CH2-, -C(O)NH-, -C(O)N(CH3)-, -NHC(O)- and -N(CH3)C(O)-.
In yet a further aspect X is a linker group selected from -NHCH2-, -N(CH3)CH2-, -OCH2-, -OCH(CH3)-, -OC(CH3)2-, -SCH2-, -SCH(CH3)-, -SC(CH3)2-, -S(O)CH2-, -S(O)CH(CH3)-, -S(O)C(CHs)2-, -S(O)2CH2-, -S(O)2CH(CH3)- and -S(O)2C(CHs)2-. In yet a further aspect X is a linker group selected from -NHCH2-, -N(CH3)CH2-,
-OCH2-, -SCH2- and -S(O)2CH2-.
In another aspect X is -SCH2- or -S(O)2CH2-.
In another aspect X is -SCH2-, -SCH(CH3)- or -SC(CH3)2-.
In another aspect X is -S(O)CH2-, -S(O)CH(CH3)- or -S(O)C(CH3)2-. In another aspect X is -S(O)2CH2-, -S(O)2CH(CH3)- or -S(O)2C(CH3)2-.
In another aspect X is -S(O)2CH2-.
In another aspect X is -S(O)2C(CH3)2-.
El
In one aspect of the invention R1 is a group selected from C^alkyl, C3- locycloalkyl, aryl, C3.iocycloalkylCi--<alkyl, arylC1.4a.kyl, cycloheteroalkyl, heteroaryl, cycloheteroalkylCualkyl, heteroarylCi-4alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R9, -OR9, -COR9, - CONR9R10, -NR9R10 and -NR9COR10.
In another aspect, R1 is a group selected from adamantyl, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyriniidinyl, pyrazinyl, pyiTolidinylmethyl, pyrrolidinylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, pyrazolylethyl, furanylmethyl, furanylethyl, thienylmethyl, thienylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl, pyrimidinylethyl, pyrazinylmethyl and pyrazinylethyl, which group is optionally substituted by 1, 2 or 3 substituent group selected from halo, cyano, nitro, RQ, - OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10.
In a further aspect, R1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONH2 and -CONHCH3.
In yet another aspect R1 is a group selected from methyl, isopropyl, cyclopropyl, cyclohexyl, -CH2CH2OH, -, -CH2CH2NC(O)CH3, phenyl, 4-fluorophenyl, 2-chlorophenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 2-methylphenyl, 4-acetamidophenyl, 4- aminophenyl, , pyiϊdin-4-yl, pyridin-2-yl, 2-oxopyrolidin-3-yl,, thiazol-2-yl, 4- methylthiazol-2-yl, and 3-methyl-l,3,4-thiadiazol-2-yl.
In yet another aspect R1 is methyl.-
X-R1 In one embodiment X-R1 is -C(CH3)2OH or -CH2OH.
In one embodiment X-R1 is -CH2OH.
E!
In one aspect of the invention R is selected from carbocyclyl or heterocyclyl which group is substituted by -NR17SO2R18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R1 ', -OR1 \ -COR1 \ - CONR11R12, -NR11R12 and -NR11COR12. In one aspect of the invention R2 is selected from carbocyclyl or heterocyclyl which group is substituted by -NHSO2R18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R1 1, -OR11, -COR11, - CONR11R12, -NR11R12 and -NR11COR12. s In one aspect of the invention R" is selected from 5 or 6 membered carbocyclyl or
1 *7 I S heterocyclyl which group is substituted by -NR SO2R and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R1 1, -OR11, -COR1 1, -CONR11R12, -NR1 1R12 and -NR11COR12.
In one aspect of the invention R2 is selected from 5 or 6 membered carbocyclyl oro heterocyclyl which group is substituted by -NHSO2R18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R1 , -OR11, -COR11, -CONR11R12, -NR11R12 and -NR11COR12.
In one aspect of the invention R2 is selected from a 6 membered aryl and 5 or 6 membered heteroaryl which group is substituted by -NR17SO2R18 and optionallys substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, -NR11R12 and -NR11COR12.
In one aspect of the invention R2 is selected from a 6 membered aryl and 5 or 6 membered heteroaryl which group is substituted by -NHSO2R and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11,Q -OR11, -COR11, -CONR11R12, -NR11R12 and -NR11COR12.
In another aspect R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is substituted by -NR17SO2R18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R1 1, -OR1 1, -COR11, -CONR11R12,5 -NR11R12 and -NR1 ' COR12.
In another aspect R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is substituted by -NHSO2R18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -COR1 1, -CONR11R12, -NR1 1R12 and0 -NR1 1COR12.
In another aspect R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is substituted by -NR17SO2R18 and optionally substituted by one or more substituent group independently selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON(CH3)2.
In another aspect R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is substituted by -NHSO2R18 and optionally substituted by one or more substituent group independently selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON(CH3)2.
In another aspect R2 is phenyl or pyridylsubstituted by -NR17SO2R18 and optionally substituted by one or more substituent group independently selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON(CH3)2.
In another aspect R is phenyl or pyridyl substituted by -NHSO2R and optionally substituted by one or more substituent group independently selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON(CH3)2.
In another aspect R2 is phenyl substituted by -NHSO2R18 and optionally substituted by one or more substituent group independently selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON(CH3)2.
In another aspect R2 is phenyl or pyridyl optionally substituted by -NR17SO2R18. In another aspect R is phenyl or pyridyl optionally substituted by -NHSO2R .
In another aspect R2 is
Figure imgf000040_0001
wherein A1 and A2 are selected from CH or N provided that at least one of A1 or A2 is CH. In another aspect R2 is
Figure imgf000040_0002
wherein A1 and A2 are selected from CH or N provided that at least one of A1 or
A" is CH H..
E4.
In one aspect of the invention R is hydrogen or methyl. In another aspect R4 is hydrogen.
Rl and R^
In another aspect of the invention, when X is -NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7-, -NR4S(O)2CR6R7-, -NR4C(O)-, -NR4C(O)NR5- Or -NR4S(O)2-, R1 and R4 together with the atom or atoms to which they are attached form a 5- to 10- membered heterocyclic ring wherein 1, 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-όalkyl, Q-galkoxy, haloCi-6alkyl, haloCi- βalkoxy, hydroxyCi-βalkyl, hydroxyCi.6alkoxy,
Figure imgf000041_0001
amino, Ci_6alkylamino, bis(Ci-6alkyl)amino, aminoC1-6alkyl, (Ci-6alkyl)aminoCt.oalkyl,s bis(Ci.6alkyl)aminoCi.6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, d-ealkylsulfony^Ci-βalky^amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci-6alkanoyl(Ci-6alkyl)amino, carbamoyl, Ci.6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.
In another aspect of the invention, when X is -NR4CR6R7-, -NR4C(O)CR6R7-,0 -NR4C(O)NR5CR6R7-, -NR4S(O)2CR6R7-, -NR4C(O)-, -NR4C(O)NR5- or -NR4S(O)2-, R1 and R4 together with the atom or atoms to which they are attached form a 5- or 6- membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci^alkyl, Ci-6alkoxy, haloCi-βalkyl, haloCi-6alkoxy, 5 hydroxyCi_6alkyl, hydroxyCi-δalkoxy, Ci-6alkoxyCi-6alkyl, C1-6alkoxyCi-6alkoxy, amino, Ci-(>alkylamino, bis(Ci-6alkyi)amino, aminoC^alkyl, (Ci-6alkyl)aminoCi-6alkyl, bis(Ci. 6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci- 6alkylsulfonyl(Ci-6alkyl)amino, sulfamoyl, Ci_6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-balkanoylamino, Ci_6alkanoyl(Ci-6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl ando bis(Ci_6alkyl)carbamoyl.
In one aspect of the invention R5 is hydrogen or methyl. In another aspect R3 is hydrogen. In another aspect R5 is methyl.
B!
In one aspect of the invention R6 is hydrogen or methyl. In another aspect R is hydrogen.
In another aspect R6 is methyl.
El
In one aspect of the invention R7 is hydrogen or methyl. In another aspect R7 is hydrogen, In another aspect R7 is methyl.
In one aspect of the invention Rs is hydrogen or halo. In another aspect R8 is hydrogen or fluoro. In a further aspect R8 is hydrogen.
In one aspect of the invention R9 is hydrogen or CMalkyl optionally substituted by 1, 2 or 3 substituent groups selected from halo, cyano, nitro, hydroxy, Ci.4alkoxy, amino, Cmalkylamino and bis(Ci-4alkyl)amino.
In another aspect R9 is hydrogen or Ci_4alkyl optionally substituted by 1, 2 or 3 halo substituents.
In a further aspect R9 is hydrogen, methyl or trifluoromethyl.
In one aspect of the invention R10 is hydrogen.
In one aspect of the invention R1 ' is hydrogen or a group selected from C1.4a.kyl, aiyl and cycloheteroalkyl which group is optionally substituted by 1 , 2 or 3 groups selected from halo, hydroxy and cyano.
In another aspect R11 is hydrogen, methyl optionally substituted with hydroxy or cyano, phenyl or pyrrolidinyl. In another aspect R11 is hydrogen or methyl.
R12
In one aspect of the invention R12 is hydrogen or methyl. R 17
In one aspect of the invention R17 is hydrogen or a group selected from C^alkyl, aiyl and cycloheteroalkyl which group is optionally substituted by 1, 2 or 3 groups selected from halo, hydroxy and cyano. In another aspect R17 is hydrogen, methyl optionally substituted with hydroxy or cyano, phenyl or pyrrolidinyl.
In another aspect R17 is hydrogen or methyl.
In another aspect R is hydrogen.
In one aspect of the invention R18 is hydrogen or a group selected from Cι.6alkyl,
C3.6cycloakyl, aryl, heteroaryl, arylCi-ealkyl and heteroarylCi-6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C galley 1,
Figure imgf000043_0001
hydroxyCi-ealkoxy, Ci.6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci.6alkyl)amino, aminoCi-6alkyl, (Ci.6alkyr)aminoCi-6alkyl, bis^i-δalky^aminoC!. 6alkyl, cyanoCi-ealkyl, Ci-6alkylsulfonyl, Ci.όalkylsulfonylamino, Ci-όalkylsulfony^C!. 6alkyl)amino, sulfamoyl, Ci^alkylsulfamoyl, bis(Ci.6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci.6alkanoyl(Ci-0alkyl)amino, carbamoyl, Ci_6alkylcarbamoyl and bis(Ci- 6alkyl)carbamoyl. In one aspect of the invention R 8 is hydrogen or a group selected from Ci-6alkyl,
C3-6cycloakyl, phenyl, naphthyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, azaindolyl, indolyl, quinolinyl, benzimidazolyl, benzofuranyl, dibenzofuranyl, benzothienyl, phenylCi-6alkyl, naphthylCi- 6alkyl, pyiτolylCi-6alkyl, imidazolylCi.ealkyl, isoxazolylC1-6alkyl,
Figure imgf000043_0002
furanylC1-6alkyl, thienylCi-6alkyl, pyridinylCi-6alkyl, pyrimidinylCi-6alkyl, pyridazinylCi. 6alkyl, azaindolylCi-6alkyl, indolylQ-ealkyl, quinolinylCi-6alkyl, benzimidazolylCi-6alkyl, benzofuranylCuealkyl, dibenzofuranylCi-6alkyl, benzothienylCi-6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, Ci^allcoxy, haloCi-6alkyl, haloCi.6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-6alkoxyCi.6alkoxy, amino, Ci-6alkylamino, bis(Ci.6alkyl)amino, aminoCi-6alkyl, (Ci-6alkyl)aminoCi..όalkyl, bis(C].6alkyl)aminoCi- 6alkyl, cyanoC|.6alkyl, Ci.6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-6alkylsulfonyl(Ci. 6alkyl)amino, sulfamoyl, Ci-όalkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci-6alkanoyl(Ci.όalkyl)aniino, carbamoyl, Ci-6alkylcarbamoyl and bis(C1- 6alkyl)carbamoyl.
In one aspect of the invention R18 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazoylmethyl, isoxazolyl, pyrazolyl, pyridinyl and pyrimidinyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, Ci-βalkoxy, haloCi-όalkyl, haloCi. 6alkoxy,
Figure imgf000044_0001
hydroxyCi-όalkoxy, Ci-ealkoxyCi-όalkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-6alkyl)aminoCi-6alkyl, bis(Ci-6alkyl)aminoCi_6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Cj-galkylsulfonylamino, Ci^alkylsulfonylCCi-όalkytyamino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci.6alkyl)sulfamoyl, Ci-όalkanoylamino, Ci-6alkanoyl(Ci.6alkyl)amino, carbamoyl, Ci-ealkylcarbamoyl and bis(C i-6alky l)carbamoy 1.
1 R In one aspect of the invention R is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2(cyclopropyl), -CH2CH2NMe2, -CH(CH3)CH2OH, -C(CH3)2CH2OH,
-CH2CH2OH, -CH2CH2CH2OH, 4-methylphenyl, 4-chlorophenyl, 4- trifluoromethylphenyl, 4-flurophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, thien-2-yl, -CH2(imidazol-2-yl), -CH2(imidazol-3-yl), isoxazolyl-3-yl, 6-oxo-lH-pryrdin-2-yl, 5- methylisoxazol-3-yl, l-methylpyrazol-4-yl, 6-methoxypryridin-3-yl, 5-fluoropyridin-2-yl, pyrimidin-2-yl, and lH-pyrazol-3-yl.
In one aspect of the invention R is hydrogen or a group selected from methyl, ethyl, propyl, butyl, cyclopropyl, and 4-flurophenyl. In one aspect of the invention there is provided a subset of compounds of formula
(I), or a pharmaceutically acceptable saltthereof; m is 0, 1 or 2;
1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is
CR8; X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-,
-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)NR5CR6R7-, -S(O)2NR4CR6R7-, -NR4C(O)-,
-S(O)2NR4- and -NR4S(O)2-; R1 is a group selected from Ci-6alkyl, carbocyclyl, carbocyclylC|.6alkyl, heterocyclyl and
Figure imgf000045_0001
which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and
-NR9COR10; or X-R1 is -C(CH3)2OH or -CH2OH;
R2 is selected from aryl and heteroaryl which group is substituted by -NR 7SO2R18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, -NR11R12 and -NR11COR12; each R3, when present, is methyl; R4 and R5 are independently hydrogen or Ci-6alkyl; or, when X is -NR4CR6R7-, -NR4C(O)NR5CR6R7-, -NR4C(O)- or -NR4S(O)2-, R1 and R4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl,
Figure imgf000045_0002
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi.ealkyl, hydroxyCi-6alkoxy, Ci-galkoxyCi-όalkyl,
Figure imgf000045_0003
amino, Ci-6alkylamino, bis(C1-6alkyl)amino, aminoCi-6alkyl, (Ci-6alkyl)aminoCi.6alkyl,
Figure imgf000045_0004
6alkyl,
Figure imgf000045_0005
Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci.6alkylsulfonyl(Ci.
6alkyl)amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci.6alkyl)sulfamoyl, d-6alkanoylamino, Ci.6alkanoyl(Ci.6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and Hs(Ci- 6alkyl)carbamoyl;R6 and R7 are independently selected from hydrogen, halo, cyano, nitro and Ci-6alkyl;
R8 is selected from hydrogen, halo, cyano and
Figure imgf000045_0006
R9 and R10 are independently hydrogen or a group selected from Ci-6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-βalkyl, Ci-6alkoxy, haloCi-6alkyl, haloCi.
6alkoxy, hydroxyCi^alkyl, hydroxyCi.6alkoxy, Ci-6alkoxyCι.6alkyl, Ci.6alkoxyCi-6alkoxy, amino, Ci-δalkylamino and bis(Ci-6alkyl)amino;
R11, R12 and R17 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, C^alkoxy, haloCi. ealkyl, haloCi-όalkoxy, hydroxyCi-6alkyl, hydroxyCi-όalkoxy, Ci-όalkoxyCi-όalkyl, Cj-
6alkoxyCi-6alkoxy, amino, Ci-6alkylamino and bis(Ci-6alkyl)amino; and
R18 is hydrogen or a group selected from Ci-6alkyl, C3.6cycloakyl, aryl, heteroaryl, arylCi. 6alkyl and heteroarylCi-δalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy,
Figure imgf000046_0001
Ci.6alkoxy, haloCi- 6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-δalkoxy, Ci-6alkoxyCi-6alkyl, Ci- 6alkoxyCi_6alkoxy, amino, Ci-6alkylamino, bis(Ci,6alkyl)amino, aminoCi^alkyl, (Ci- 6alkyl)aminoCi-6alkyl, bis(Ci-6alkyl)aminoCi.6alkyl, cyanoCi.6alkyl, Ci-6alkylsulfonyl, C1- 6alkylsulfonylamino, Ci-6alkylsulfonyl(Ci.6alkyl)amino, sulfamoyl,
Figure imgf000046_0002
bis(Ci.6alkyl)sulfamoyl, Ci-βalkanoylamino, Ci-6alkanoyl(Cι.6alkyl)amino, carbamoyl, Ci- 6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.
In another aspect of the invention there is provided a subset of compounds of formula (I), or a pharmaceutically acceptable salt thereof; m is 0, 1 or 2;
1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is
CR8;
X is a linker group selected from -NR4CH2-, -OCH2-, -OCH(CH3)-, -OC(CH3)2-, -SCH2-,
-SCH(CH3)-, -SC(CH3)2-, -S(O)CH2-, -S(O)CH(CH3)-, -S(O)C(CH3)2-, -S(O)2CH2-, -S(O)2CH(CH3)-, -S(O)2C(CH3)2-, -C(O)NR4- and -NR4C(O)-;
R1 is a group selected from adamantyl, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, pyrazolylethyl, furanylmethyl, furanylethyl, thienylmethyl, thienylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl, pyrimidinylethyl, pyrazinylmethyl and pyrazinylethyl, which group is optionally substituted by 1, 2 or 3 substituent group selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10; or X-R1 is -C(CH3)2OH or -CH2OH; R2 is selected from 5 or 6 membered aryl and heteroaryl which group is substituted by -NHSO2R18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, -NR11R12 and
-NR11COR12; each R3, when present, is methyl;
R4 is hydrogen or Ci-6alkyl; or, when X is -NR4CH2- or -NR4C(O)-, R1 and R4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C^alkyl, Ci.6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi^alkoxy, Ci-6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci- 6alkyl)aminoCi-6alkyl, bis(Ci.6alkyl)aminoCi-6alkyl, cyanoCi^alkyl, Ci-6alkylsulfonyl, C1- όalkylsulfonylamino, Ci-6alkylsulfonyl(C1-6alkyl)amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci.6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci.6alkanoyl(Ci.(5alkyl)amino, carbamoyl, C1- 6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R8 is selected from hydrogen, halo, cyano and
Figure imgf000047_0001
R9 and R10 are independently hydrogen or a group selected from Ci-6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci.6alkyl, Ci-6alkoxy, haloCi-6alkyl, haloCi. 6alkoxy, hydiOxyCi-6alkyl, hydroxyCi.6alkoxy, Ci-6alkoxyC1-6alkyl, Ci-6alkoxyCi.6alkoxy,0 amino, Ci-6alkylamino and bis(Ci-6alkyl)amino;
R11 and R12 are independently hydrogen or a group selected from C1-6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, Ci.6alkoxy, haloCi-6alkyl, haloCi- όalkoxy, hydiOxyCi-6alkyl, hydroxyCi.6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-6alkoxyC1-6alkoxy,S amino, C1-6alkylamino and bis(Ci-6alkyl)amino; and
R18 is hydrogen or a group selected from Ci^alkyl, C3-6cycloakyl, aryl, heteroaiyl, arylCi- 6alkyl and heteroarylCi.όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-ealkyl, Ci-6alkoxy, haloCi- 6alkyl, haloCi-6alkoxy, hydroxyCi^alkyl, hydroxyCi.ealkoxy, Ci-όalkoxyCi-δalkyl, Ci-o 6alkoxyC|.6alkoxy, amino, Ci-6alkylamino, bis(Ci.6alkyl)amino, aminoCi-6alkyl, (Ci- 6alkyl)aminoCi-6alkyl,
Figure imgf000047_0002
cyanoCi-6alkyl, Ci-ealkylsulfonyl, Ci- όalkylsulfonylamino, Ci-6alkylsulfonyl(Ci-6alkyi)amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci.6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci.6alkanoyl(Ci-(5alkyl)amino, carbamoyl, Ci-
6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.
In another particular class of compound of formula (I), or a pharmaceutically acceptable salt thereof; m is O orl;
1Y is CH and Y2 is N;
X is a linker group selected from -S(O)2CH2-, -S(O)2CH(CH3)- and -S(O)2C(CH3V;
R1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONH2 and -CONHCH3; or -XR1 is -C(CH3)2OH or -CH2OH; R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl and thiazolyl which group is substituted by -NHSO2R and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, -NR1 1R12 and -NR11COR12;
R3, when present, is methyl; R11 and R12 are independently hydrogen or a group selected from
Figure imgf000048_0001
carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, Ci-6alkoxy, haloCi-6alkyl, haloCi.
6alkoxy, hydroxyCi-(3alkyl, hydroxyCi.6alkoxy, Ci.6alkoxyCi-0alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci.6alkylamino and Ms(Ci -6alkyl)amino; and R18 is hydrogen or a group selected from C1-6alkyl, C3-6cycloakyl, aryl, heteroaryl, arylCj.
6alkyl and heteroaiylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, Ci-όalkoxy, haloQ. ealkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-βalkoxy,
Figure imgf000048_0002
Ci-
6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-(,alkyl, (Ci- 6alkyl)aminoCi-6alkyl, bis(Ci_6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci- 6alkylsulfonylamino, Ci.6alkylsulfonyl(Ci.6alkyl)amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci-6alkaiioyl(Ci-6alkyi)amino, carbamoyl, Ci- δalkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.
In a further particular class of compound of formula (I), or a pharmaceutically acceptable salt thereof; m is 1 ;
X is a linker group selected from -S(O)2CH2-, -S(O)2CH(CH3)- and -S(O)2C(CH3)2-;
1Y is CH and Y2 is N.
R1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONH2 and -CONHCH3;
R2 is phenyl or pyridyl substituted by -NHSO2R18 and optionally substituted by one or more substituent group independently selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON(CH3)2;
R3is methyl; and
R18 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t- butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazoylmethyl, isoxazolyl, pyrazolyl, pyridinyl and pyrimidinyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, Ci-όalkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-όalkoxy, Ci-6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci.6alkyl)amino, ammoCi-βalkyl,
Figure imgf000049_0001
bis(C1-6alkyl)aminoCi. 6alkyl,
Figure imgf000049_0002
Ci-ealkylsulfonyl, Ci.ealkylsulfonylamino, Ci-6alkylsulfonyl(Ci_
6alkyl)amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Ci_6alkanoyl(Ci-6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and Ms(Ci-
6alkyl)carbamoyl.
In a further particular class of compound of formula (I), or a pharmaceutically acceptable salt thereof; m is 1;
X is a linker group selected from -S(O)2CH2-, -S(O)2CH(CH3)- and -S(O)2C(CH3)2-; 1Y is CH and Y2 is N.
R1 is a group selected from methyl, isopropyl, cyclopropyl, cyclohexyl, -CH2CH2OH, -CH2CH2NC(O)CH3, phenyl, 4-fluorophenyl, 2-chlorophenyl, 2-trifluoromethylphenyl, 2- methoxyphenyl, 2-methylphenyl, 4-acetamidophenyl, 4-aminophenyl, pyridin-4-yl, pyridin-2-yl, 2-oxopyrolidin-3-yl,, thiazol-2-yl, 4-methylthiazol-2-yl, and 3 -methyl- 1,3,4- thiadiazol-2-yl; R2 is
Figure imgf000050_0001
wherein A1 and A2 are selected from CH or N provided that at least one of A1 or A2 is CH;
R17 is hydrogen;
R18 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH?(cyclopropyl), -CH2CH2NMe2, -CH(CH3)CH2OH, -C(CH3)2CH2OH, -CH2CH2OH,
-CH2CH2CH2OH, 4-methylphenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4-flurophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, thien-2-yl, -CH2(imidazol-2-yl), -CH2(imidazol-3-yl), isoxazolyl-3-yl, 6-oxo-lH-piyrdin-2-yl, 5-methylisoxazol-3-yl, l-methylpyrazol-4-yl,
6-methoxypiyridin-3-yl, 5-fluoropyridin-2-yl, pyrimidin-2-yl, and lH-pyrazol-3-yl; and, R3is methyl. In one aspect of the invention there is provided a subset of compounds of formula (Ia) or (Ib)
Figure imgf000051_0001
or a pharmaceutically acceptable salt thereof;
1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is CR8;
X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-,
-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)NR5CR6R7-, -S(O)2NR4CR6R7-, -NR4C(O)-,
-S(O)2NR4- and -NR4S(O)2-;
R1 is a group selected from Cι-6alkyl, carbocyclyl, carbocyclylCi-όalkyl, heterocyclyl and heterocyclylCi-6alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and
-NR9COR10; or X-R1 is -C(CH3)2OH or -CH2OH;
R2 is selected from aryl and heteroaryl which group is substituted by -NR17SO2R18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR1 1, -COR1 1, -CONR11R12, -NR11R12 and -NR11COR12;
R3 is methyl;
R4 and R5 are independently hydrogen or
Figure imgf000051_0002
or, when X is -NR4CR6R7-, -NR4C(O)NR5CR6R7-, -NR4C(O)- or -NR4S(O)2-, R1 and R4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-balkyl, Ci-6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxy C i-6alkoxy, Ci-όalkoxyCi-βalkyl, Ci-6alkoxyCi-balkoxy, amino, d-όalkylamino, bis(Ci-όalkyl)amino, aminoC|.6alkyl, (Ci-6alkyl)aminoCi.6alkyl, bis(Ci-6alkyl)aminoCi. βalkyl, cyanoCi-ealkyl, Ci^alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-6alkylsulfonyl(C|.
6alkyl)amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci.balkanoyl(Ci.6alkyl)amino, carbamoyl, Ci-όalkylcarbamoyl and Ms(Ci-
6alkyl)carbamoyl;
R6 and R7 are independently selected from hydrogen, halo, cyano, nitro and Ci^alkyl;
R8 is selected from hydrogen, halo, cyano and
Figure imgf000052_0001
R9 and R10 are independently hydrogen or a group selected from C1-6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci.6alkyl, Ci-6alkoxy, haloCi-balkyl, haloCi. balkoxy, hydroxyCi-όalkyl, hydroxyCi^alkoxy, Ci-6alkoxyCi.6alkyl, C1-baikoxyCi-6alkoxy, amino, Ci-ealkylamino and bis(Ci_6alkyl)amino; R11, R12 and R17 are independently hydrogen or a group selected from C|-6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, Ci-6alkoxy, haloCi- ealkyl, haloCi.6alkoxy, hydroxyCi-balkyl, hydroxyCi-όalkoxy, Ci-6alkoxyCi.6alkyl, C1- ealkoxyd-όalkoxy, amino, Ci-6alkylamino and bis(Ci-6alkyl)amino; and
R18 is hydrogen or a group selected from Ci-6alkyl, C3-6cycloakyl, aryl, heteroaryl, arylCi- 6alkyl and heteroaiylCi-6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, C1-6alkoxy, haloCi- 6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi.6alkyl, Ci- 6alkoxyC1-6alkoxy, amino, C1-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-ealkyl, (Ci- 6alkyl)aminoCi-6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci_6alkylsulfonyl, C1- όalkylsulfonylamino, Ci-6alkylsulfonyl(Ci.6alkyl)amino, sulfamoyl, C]-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci-6alkanoyl(C1-6alkyl)amino, carbamoyl, Ci- 6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl. In another aspect of the invention there is provided a subset of compounds of formula (Ia) or (Ib)
Figure imgf000053_0001
(Ia) (Ib) or a pharmaceutically acceptable salt thereof;
Y and Y are independently N or CR provided that one of 1Y and Y2 is N and the other is CR8;
X is a linker group selected from -NR4CH2-, -OCH2-, -OCH(CH3)-, -OC(CH3)2-, -SCH2-, -SCH(CH3)-, -SC(CH3),-, -S(O)CH2-, -S(O)CH(CH3)-, -S(O)C(CH3V, -S(O)2CH2-, -S(O)2CH(CH3)-, -S(O)2C(CH3V, -C(O)NR4- and -NR4C(O)-; R1 is a group selected from adamantyl, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, pynOlidinylmethyl, pyrrolidinylethyl, pyrrolylmethyl, pyiτolylethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, pyrazolylethyl, furanylmethyl, furanylethyl, thienylmethyl, thienylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl, pyrimidinylethyl, pyrazinylmethyl and pyrazinylethyl, which group is optionally substituted by 1, 2 or 3 substituent group selected from halo, cyano, nitro, RQ, -OR9, -C0Rq, -CONR0R10, -NR9R10 and -NR9COR10; or X-R1 is -C(CH3)2OH or -CH2OH;
R2 is selected from 5 or 6 membered aryl and heteroaiyl which group is substituted by -NHSO2R18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, -NR11R12 and -NR11COR12; R3 is methyl;
R4 is hydrogen or Ci.6alkyl; or, when X is -NR4CH2- or -NR4C(O)-, R1 and R4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, Ci-6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi.6alkoxy,
Figure imgf000054_0001
Ci-6alkoxyCi-6alkoxy, amino, Ci-6alkylaniino, bis(Ci_6alkyl)amino, aminoCi-6alkyl, (Ci- 6alkyl)aminoC1-6alkyl, bis(Ci.6alkyl)aminoCi.6alkyl, cyanoCi-6alkyl,
Figure imgf000054_0002
Ci- ήalkylsulfonylamino, Cι.6alkylsulfonyl(Ci-6alkyl)amino, sulfamoyl, Ci-δalkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci.ealkanoylamino, Ci.6alkanoyl(Ci.6alkyl)amino, carbamoyl, Ci- 6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R8 is selected from hydrogen, halo, cyano and Ci-6alkyl;
R9 and R10 are independently hydrogen or a group selected from Ci^alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C^alkyl, Ci-6alkoxy, halod^alkyl, haloCi- δalkoxy, hydroxyCi-5alkyl, hydroxyCi-6alkoxy, Ci-ealkoxyCi-όalkyl, Ci-όalkoxyCi-όalkoxy, amino, Cj-όalkylamino and bis(C[.6alkyl)amino;
R11 and R12 are independently hydrogen or a group selected from Ci^alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl,
Figure imgf000054_0003
haloCi-6alkyl, haloCi. 6alkoxy,
Figure imgf000054_0004
hydroxyCi-balkoxy, C1-6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-galkylamino and bis(Ci.6alkyl)amino; and
R18 is hydrogen or a group selected from Ci-6alkyl, C3-6cycloakyl, aryl, heteroaiyl, arylQ. 6alkyl and heteroarylCi-6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, C1-6alkoxy, haloCi- ealkyl, haloCi-6alkoxy, hydiOxyCi-6alkyl, hydroxyCi-6alkoxy, Ci.6alkoxyCi-6alkyl, Ci- 6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (C1- 6alkyl)aminoCi-6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-ealkyl, Ci.6alkylsulfonyl, Ci- 6alkylsulfonylamino, Ci-6alkylsulfonyl(Ci.6alkyl)amino, sulfamoyl, Ci_6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci-6alkanoyl(Ci-6alkyl)amino, carbamoyl, Ci- όalkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.
In another particular class of compound of formula (Ia) or (Ib),
Figure imgf000055_0001
(Ia) (Ib) or a pharmaceutically acceptable salt thereof;
1Y is CH and Y2 is N; X is a linker group selected from -S(O)2CH2-, -S(O)2CH(CH3)- and -S(O)2C(CH3)2-;
R1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONH2 and -CONHCH3; or -XR1 is -C(CH3)2OH or -CH2OH;
R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl and thiazolyl which group is substituted by -NHSO2R18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, -NR11R12 and -NR11COR12;
R3 is methyl;
R11 and R12 are independently hydrogen or a group selected from Ci-6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, Ci-6alkoxy, haloCi-6alkyl, haloCj.
6alkoxy, hydroxyCi-6alkyl, hydroxyC1-6alkoxy, Ci-6alkoxyCi.6alkyl, Q-όalkoxyCi-όalkoxy, amino, Ci-6alkylamino and bis(Ci-6alkyl)amino; and
R18 is hydrogen or a group selected from Ci-6alkyl, C3-6cycloakyl, aryl, heteroaryl, arylCi. balkyl and heteroarylCi-6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci^alkyl, Ci-6alkoxy, haloCi- ealkyl,
Figure imgf000055_0002
hydroxyC1-6alkyl, hydroxyCi.6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-
6alkoxyC|-6alkoxy, amino, Ci-balkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci- 6alkyl)aminoCi.6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl,
Figure imgf000056_0001
Ci- όalkylsulfonylamino, Ci.6alkylsulfonyl(Ci-6alkyl)amino, sulfamoyl, C1-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci.6alkanoylamino, Ci_6alkanoyl(Ci-6alkyl)amino, carbamoyl, Ci- 6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.
In a further particular class of compound of formula (Ia) or (Ib)
Figure imgf000056_0002
or a pharmaceutically acceptable salt thereof; X is a linker group selected from -S(O)2CH2-, -S(O)2CH(CH3)- and -S(O)2C(CHs)2-; 1Y is CH and Y2 is N.
R1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, pyridinyl, pyrazolylethyl, furanylniethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONH2 and -CONHCH3;
R is phenyl or pyridyl substituted by -NHSO2R and optionally substituted by one or more substituent group independently selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON(CH3)2; R3 is methyl; and
R18 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t- butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazoylmethyl, isoxazolyl, pyrazolyl, pyridinyl and pyrimidinyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, Ci.6alkoxy, haloCi-6alkyl, haloCi.6alkoxy,
Figure imgf000056_0003
hydroxyCi-βalkoxy, Ci.6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-δalkylamino, bis(Ci-6alkyl)amino, aminoCi_6alkyl, (Ci.6alkyl)aminoCi-6alkyl, bis(Ci-6alkyl)aminoCi. 6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino,
Figure imgf000057_0001
6alkyl)amino, sulfamoyl, Ci-ealkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-όalkanoylamino, Ci-6alkanoyl(Ci-6alkyl)amino, carbamoyl,
Figure imgf000057_0002
and bis(C[. 6alkyl)carbamoyl.
In a further particular class of compound of formula (Ia) or (Ib)
Figure imgf000057_0003
or a pharmaceutically acceptable salt thereof; m is 1 ; X is a linker group selected from -S(O)2CH2-, -S(O)2CH(CH3)- and -S(O)2C(CH3)2-;
1Y is CH and Y2 is N.
R1 is a group selected from methyl, isopropyl, cyclopropyl, cyclohexyl, -CH2CH2OH,
-CH2CH2NC(O)CH3, phenyl, 4-fluorophenyl, 2-chlorophenyl, 2-trifluoiOmethylphenyl,
2-methoxyρhenyl, 2-methylphenyl, 4-acetamidophenyl, 4-aminophenyl, pyridin-4-yl, pyridin-2-yl, 2-oxopyrolidin-3-yl,, thiazol-2-yl, 4-methylthiazol-2-yl, and
3 -methy 1- 1 ,3 ,4-thiadiazol-2-yl;
R2 is
Figure imgf000057_0004
wherein A1 and A2 are selected from CH or N provided that at least one of A1 or A2 is CH;
R17 is hydrogen; and
R18 is hydrogen or a group selected from methyl, ethyl, propyl, i- propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2(cyclopropyl), -CH2CH2NMe2, -CH(CH3)CH2OH, -C(CHs)2CH2OH, -CH2CH2OH, -CH2CH2CH2OH, 4-methylphenyl, 4-chlorophenyl, 4-trifluoroniethylphenyl, 4-flurophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, thien-2-yl, -CH2(imidazol-2-yl), -CH2(imidazol-3-yl), isoxazolyl-3-yl, 6-oxo-lH-piyrdin-2-yl,
5-methylisoxazol-3-yl, l-methylpyrazol-4-yl, 6-methoxypryridin-3-yl, 5-fluoropyridin-2-yl, pyrimidin-2-yl, and lH-pyrazol-3-yl; and, R3 is methyl. Another aspect of the invention provides a compound, or a combination of compounds, selected from any one of the Examples or a pharmaceutically acceptable salt thereof.
The invention also provides processes for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof. A compound of formula (I), wherein X = -S(O)2CR6R7-, may be prepared by oxidising a compound of the formula (I), wherein X = SCR6R7-, for example by using Oxone® at room temperature in a mixed solvent system of water and ethanol
Figure imgf000058_0001
A compound of formula (I), wherein R X = R OCR R -, may be prepared by the reaction of a compound of formula (I), wherein R1X = HOCR6R7-, with a compound of formula (II), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.) optionally in the presence of a suitable base such as triethylamine and a solvent such as tetrahydrofuran or N, iV-dimethylformamide.
Figure imgf000058_0002
A compound of formula (I), wherein R1X = R1R4NCR6R7-, may be prepared by the reaction of a compound of formula (I), wherein R1X = HR4NCR6R7-, with a compound of formula (II), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.) optionally in the presence of a suitable base such as triethylamine and a solvent such as tetrahydrofuran or iV.N-dimethylformamide; or by the reaction of a compound of formula (I), wherein R1X = HR4NCR6R7-, with a compound of formula (III) in the presence of a suitable reducing agent such as NaCNBH3.
Figure imgf000059_0001
A compound of formula (I), wherein X1 = -S(O)2CR6R7-, -SCR6R7-, -OCR6R7-, - R4NCR6R7-, -S(O)CR6R7-, may be prepared by the reaction of a compound of formula (IV), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.), with a compound of formula (V) optionally in the presence of a suitable base such as triethylamine and a solvent such as tetrahydrofuran or N,iV-dimethylformamide.
Figure imgf000059_0002
A compound of formula (I), wherein X = -SCR0R7-, may be prepared by the reaction of a compound of formula (IV), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.), with thiourea in a suitable solvent such as ethanol to generate a compound of formula (VI) which is then subsequently reacted with a compound of formula (II) in the presence of a suitable base such as sodium hydroxide and a solvent such as ΛζiV-dimethylformamide.
Figure imgf000060_0001
reaction of a compound of formula (VII) with an amine of formula R1R4NH following the suitable activation of the carboxylic acid by methods known in the literature such as the use of a coupling agent such as HATU or the conversion to an acyl chloride.
Figure imgf000060_0002
A compound of formula (I), wherein X = -S(O)2CR6R7-, may be prepared by the sequential reaction of a compound of formula (I), wherein X = -S(O)2CH2-, with a compound of formula (VIII) followed by reaction with a compound of formula (IX), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.), in the presence of a suitable base such as sodium hydride or potassium tø/'f-butoxide in a suitable solvent such as tetrahydrofuran or N, JV-dimethylformamide.
A compound of formula (I), wherein R1X = HOCR6R7-, may be prepared by the reaction of a compound of formula (X), with suitable organometallic reagents of fomula (XI) and formula (XII) such as the grignard reagent in a suitable solvent. Where R6 and R7 are different then it may be possible to use techniques known in the literature such the conversion of a compound of formula (X) to the Weinreb amide and reaction with an organometallic reagent of formula (XI) and then reaction with an organometallic reagent of formula (XII) in a subsequent step.
Figure imgf000061_0001
A compound of formula (I) may be prepared from a compound of formula (XIII), wherein L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)2Me etc.), with a suitable organometallic reagent (such as the boronic acid R2B(OH)2 or the boronic ester R2B(OR)2 etc.) in the presence of a suitable metal catalyst (such as palladium or copper) in a suitable solvent such as 1,4-dioxane. Alternatively where R2 connects to the pyrimidine ring through a nitrogen, oxygen or sulphur atom a compound of formula (I) may be prepared from a compound of formula (XIII), wherein L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)2Me etc.), by reaction with the required amine, alcohol or thiol in the presence of a suitable base such as potassium carbonate in a suitable solvent such as
Figure imgf000061_0002
(XlIl) (O
It will be appreciated that a compound of formula (XIII) may be transformed into another compound of formula (XIII) by techniques such as oxidation, alkylation, reductive amination etc., either listed above or otherwise known in the literature.
A compound of formula (XIII), wherein X1 = -S(O)2CR0R7-, -SCR0R7-, -OCR6R7-, -R4NCR6R7-, -S(O)CR6R7-, may be prepared by the reaction of a compound of formula (XIV), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.), with a compound of formula (V) optionally in the presence of a suitable base such as triethylamine and a solvent such as tetrahydrofuran or N, N-dimethylformamide.
Figure imgf000061_0003
A compound of formula (XIII), wherein X = -SCR6R7-, may be prepared by the reaction of a compound of formula (XIV), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.), with thiourea in a suitable solvent such as ethanol to generate a compound of formula (XV) which is then subsequently reacted with a compound of formula (II) in the presence of a suitable base such as sodium hydroxide and a solvent such as iV,iV-dimethylformamide.
Figure imgf000062_0001
A compound of formula (XIII), wherein X = -R4NC(O)-, may be prepared by the reaction of a compound of formula (XVI) with an amine of formula R1R NH following the suitable activation of the carboxylic acid by methods known in the literature such as the use of a coupling agent such as HATU or the conversion to an acyl chloride.
Figure imgf000062_0002
A compound of formula (XIII), wherein X = -S(O)2CR6R7-, may be prepared by the sequential reaction of a compound of formula (XIII), wherein X = -S(O)2CH2-, with a compound of formula (VIII) followed by reaction with a compound of formula (IX), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.), in the presence of a suitable base such as sodium hydride or potassium tβvt-butoxido in a suitable solvent such as tetrahydrofuran or N, JV-dimethylformamide.
Figure imgf000062_0003
may be prepared by the reaction of a compound of formula (XVII), with suitable organometallic reagents of fomula (XI) and formula (XII) such as the giϊgnard reagent in a suitable solvent. Where R6 and R7 are different then it may be possible to use techniques known in the literature such the conversion of a compound of formula (XVII) to the Weinreb amide and reaction with an organometallic reagent of formula (XI) and then reaction with an organometallic reagent of formula (XII) in a subsequent step .
Figure imgf000063_0001
A compound of formula (IV) may be prepared from a compound of formula (XIV), wherein L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)2Me etc.) and L1 is a leaving group (such as halo, tosyl, mesyl etc.), with a suitable organometallic reagent (such as the boronic acid R~B(OH)2 or the boronic ester R-B(OR)2 etc.) in the presence of a suitable metal catalyst (such as palladium or copper) in a suitable solvent such as 1 ,4- dioxane. Alternatively where R connects to the pyrimidine ring through a nitrogen, oxygen or sulphur atom a compound of formula (IV) may be prepared from a compound of formula (XIV), wherein L is a leaving group (such as halo, tosyl, mesyl, -SMe, - S(O)2Me etc.), by reaction with the required amine, alcohol or thiol in the presence of a suitable base such as potassium carbonate in a suitable solvent such as N, N- dimethy If ormamide .
Figure imgf000063_0002
A compound of formula (X) may be prepared from a compound of formula (XVII), wherein L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)2Me etc.) and R is a hydrogen or C^alkyl group, with a suitable organometallic reagent (such as the boronic acid R"B(OH)2 or the boronic ester R B(OR)2 etc.) in the presence of a suitable metal catalyst (such as palladium or copper) in a suitable solvent such as 1,4-dioxane. Alternatively where R2 connects to the pyrimidine ring through a nitrogen, oxygen or sulphur atom a compound of formula (X) may be prepared from a compound of formula (XVII), wherein L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)2Me etc.), by reaction with the required amine, alcohol or thiol in the presence of a suitable base such as potassium carbonate in a suitable solvent such as iV.iV-dimethylformamide.
Figure imgf000064_0001
s A compound of formula (XVIII) may be prepared from a compound of formula
(XIX), wherein L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)2Me etc.), with a suitable organometallic reagent (such as the boronic acid R2B(OH)2 or the boronic ester R2B(OR)2 etc.) in the presence of a suitable metal catalyst (such as palladium or copper) in a suitable solvent such as 1,4-dioxane. Alternatively where R" connects to theo pyiϊmidine ring through a nitrogen, oxygen or sulphur atom a compound of formula (XVIII) may be prepared from a compound of formula (XIX), wherein L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)2Me etc.), by reaction with the required amine, alcohol or thiol in the presence of a suitable base such as potassium carbonate in a suitable solvent such as N, iV-dimethylformamide.
Figure imgf000064_0002
5 (XlX) (XVIIl)
A compound of formula (XX) may be prepared from a compound of formula (XXI), wherein L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)2Me etc.), with a suitable organometallic reagent (such as the boronic acid R2B(OH)2 or the boronic ester R2B(OR)2 etc.) in the presence of a suitable metal catalyst (such as palladium or0 copper) in a suitable solvent such as 1,4-dioxane. Alternatively where R2 connects to the pyrimidine ring through a nitrogen, oxygen or sulphur atom a compound of formula (XX) may be prepared from a compound of formula (XXI), wherein L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)2Me etc.), by reaction with the required amine, alcohol or thiol in the presence of a suitable base such as potassium carbonate in a suitable solvents such as iV,iV-dimethylformamide.
Figure imgf000065_0001
(XXI) (XX)
A compound of formula (I), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.), may be prepared by the reaction of a compound of formula (XXII) with a compound of formula (XXIII) optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as N, Af-dimethylformamide.
Figure imgf000065_0002
(XXIIi) (XXIi) (I)
It will be appreciated that a compound of formula (XXII) may be transformed into another compound of formula (XXII) by techniques such as oxidation, alkylation, reductive animation etc., either listed above or otherwise known in the literature. A compound of formula (IV), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.), may be prepared by the reaction of a compound of formula (XXIV) with a compound of formula (XXIII) optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as N, N-dimethylforrnamide.
Figure imgf000065_0004
(XXIII)
Figure imgf000065_0003
A compound of formula (X), wherein L is a leaving group (such as halo, tosyl, mesyl etc.) and R is a hydrogen or a Ci-4 alkyl group, may be prepared by the reaction of a compound of formula (XXV) with a compound of formula (XXIII) optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as N,N- dimethy lformamide .
Figure imgf000066_0002
(XXIII)
Figure imgf000066_0001
A compound of formula (XVIII), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.), may be prepared by the reaction of a compound of formula (XXVI) with a compound of formula (XXIII) optionally in the presence of a suitable base such as s triethylamine in a suitable solvent such as iV,N-dimethylformamide.
Figure imgf000066_0003
(XXVI) (XVIII)
A compound of formula (XX), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.) and L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)2Me etc.), may be prepared by the reaction of a compound of formula (XXVII) with a compound ofo formula (XXIII) optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as N, N-dimethylformaniide.
Figure imgf000066_0004
(XXlIl)
Figure imgf000066_0005
(XXVII) (XX)
A compound of formula (XIII), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.) and L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)2Me etc.),s may be prepared by the reaction of a compound of formula (XXVIII) with a compound of formula (XXIII) optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as JV,iV-dimethylformamide.
Figure imgf000066_0006
(XXiIi) (XXVIiI) (XiIi) It will be appreciated that a compound of formula (XIII) may be transformed into another compound of formula (XIII) by techniques such as oxidation, alkylation, reductive animation etc., either listed above or otherwise known in the literature.
A compound of formula (XIV), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.) and L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)2Me etc.), may be prepared by the reaction of a compound of formula (XXIX) with a compound of formula (XXIII) optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as N.N-dimethylformamide.
Figure imgf000067_0001
A compound of formula (XVII), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.) and L" is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)2Me etc.) and R is a hydrogen or a Ci-4 alkyl group, may be prepared by the reaction of a compound of formula (XXX) with a compound of formula (XXIII) optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as Λf JV-dimethylformamide.
Figure imgf000067_0002
A compound of formula (XIX), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.) and L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)2Me etc.), may be prepared by the reaction of a compound of formula (XXXI) with a compound of formula (XXIII) optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as ΛζiV-dimethylformamide.
Figure imgf000067_0003
(XXXi) (XiX) A compound of formula (XXI), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.) and L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)2Me etc.), may be prepared by the reaction of a compound of formula (XXXII) with a compound of formula (XXIII) optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as ΛζN-dimethylformamide.
Figure imgf000068_0001
(XXXII) (XXi)
A compound of formula (I), wherein R1X = H2NCH2-, may be prepared from a compound of formula (XVIII) by a reduction such as hydrogenation with hydrogen gas and a suitable catalyst such as Palladium on carbon in a suitable solvent such as ethanol.
Figure imgf000068_0002
(XVIII) O
A compound of formula (I), wherein R1X = H2NC(O)-, may be prepared from a compound of formula (XVIII) by hydrolysis with, for example, sodium hydroxide in a suitable solvent such as a water ethanol mix.
Figure imgf000068_0003
(XVIII)
Figure imgf000068_0004
A compound of formula (I), wherein R1X = H2NCR6R7-, may be prepared from a compound of formula (XVIII) by reaction with organometallic reagents (XI) and (XII).
Figure imgf000068_0005
(XVIII) (|) A compound of formula (XIII), wherein R X = H2NCH2-, may be prepared from a compound of formula (XIX) by a reduction such as hydrogenation with hydrogen gas and a suitable catalyst such as Palladium on carbon in a suitable solvent such as ethanol.
H2N R vVΛN*ΛN La
Figure imgf000069_0001
(XIX) (XIII)
A compound of formula (XIII), wherein R IvX - = H2NC(O)-, may be prepared from a compound of formula (XIX) by hydrolysis with, for example, sodium hydroxide in a suitable solvent such as a water ethanol mix.
Figure imgf000069_0002
A compound of formula (XIII), wherein R1X = H2NCR0R7-, may be prepared from a compound of formula (XIX) by reaction with organometallic reagents (XI) and (XII).
Figure imgf000069_0003
It will be appreciated that the R2 group may be introduced at any stage initially as a carbocyclic or heterocyclic amine (optionally with the nitrogen protected, such protecting groups include but are not limited to nitro, terf-butoxy carbamate etc.) which can be transformed at a subsequent stage in the synthesis (after appropriate deprotection) to a sulphonamide by the reaction with a sulphonyl chloride (or other suitably activated species) in the presence of a suitable base, or other methods of forming a sulphonamide known in the literature.
It will be appreciated that certain of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention. For example compounds of formula (I) my be converted into further compounds of formula (I) by standard aromatic substitution reactions or by conventional functional group modifications. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogen group. Particular examples of modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulfinyl or alkylsulfonyl.
It will also be appreciated that in some of the reactions mentioned herein it may be necessary /desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Conventional protecting groups may be used in accordance with standard practice (for illustration see T. W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactants include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein. A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or te/Y-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a te/t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladiuni-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vaiy with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-buty\ group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
Many of the intermediates defined herein are novel and these are provided as a further feature of the invention. Biological Assays
The following assays can be used to measure the effects of the compounds of the present invention as mTOR kinase inhibitors, as PI3 kinase inhibitors, as inhibitors in vitro of the activation of PB kinase signalling pathways and as inhibitors in vitro of the proliferation of MDA-MB-468 human breast adenocarcinoma cells. (a) In Vitro mTOR Kinase Assay
The assay used AlphaScreen technology (Gray et al. , Analytical Biochemistry, 2003, 313: 234-245) to determine the ability of test compounds to inhibit phosphorylation by recombinant mTOR. A C-terminal truncation of mTOR encompassing amino acid residues 1362 to 2549 of mTOR (EMBL Accession No. L34075) was stably expressed as a FLAG-tagged fusion in HEK293 cells as described by Vilella-Bach et al, Journal of Biochemistry, 1999, 274, 4266-4272. The HEK293 FLAG-tagged mTOR (1362-2549) stable cell line was routinely maintained at 37°C with 5% CO2 up to a confluency of 70-90% in Dulbecco's modified Eagle's growth medium (DMEM; Invitrogen Limited, Paisley, UK Catalogue No. 41966- 029) containing 10% heat-inactivated foetal calf serum (FCS; Sigma, Poole, Dorset, UK, Catalogue No. F0392), 1% L-glutamine (Gibco, Catalogue No. 25030-024) and 2 mg/ml Geneticin (G418 sulfate; Invitrogen Limited, UK Catalogue No. 10131-027). Following expression in the mammalian HEK293 cell line, expressed protein was purified using the FLAG epitope tag using standard purification techniques.
Test compounds were prepared as 10 mM stock solutions in DMSO and diluted into water as required to give a range of final assay concentrations. Aliquots (2 μl) of each compound dilution were placed into a well of a Greiner 384- well low volume (LV) white polystyrene plate (Greiner Bio-one). A 30 μl mixture of recombinant purified mTOR enzyme, 1 μM biotinylated peptide substrate (Biotin-Alix-Lys-Lys-Ala-Asn-Gln- Val-Phe-Leu-Gly-Phe-Thi--Tyr-Val-Ala-Pro-Ser-Val-Leu-Glu-Ser-Val-Lys-Glu-NH2; Bachem UK Ltd), ATP (20 μM) and a buffer solution [comprising Tris-HCl pH7.4 buffer (50 mM), EGTA (0.1 mM), bovine serum albumin (0.5 mg/mL), DTT (1.25 mM) and manganese chloride (10 mM)] was agitated at room temperature for 90 minutes. Control wells that produced a maximum signal corresponding to maximum enzyme activity were created by using 5% DMSO instead of test compound. Control wells that produced a minimum signal corresponding to fully inhibited enzyme were created by adding EDTA (83 mM) instead of test compound. These assay solutions were incubated for 2 hours at room temperature. Each reaction was stopped by the addition of 10 μl of a mixture of EDTA (50 mM), bovine serum albumin (BSA; 0.5 mg/mL) and Tris-HCl pH7.4 buffer (50 mM) containing p70 S6 Kinase (T389) 1 A5 Monoclonal Antibody (Cell Signalling Technology, Catalogue No. 9206B) and AlphaScreen Streptavidin donor and Protein A acceptor beads (200 ng; Perkin Elmer, Catalogue No. 6760002B and 6760137R respectively) were added and the
5 assay plates were left for about 20 hours at room temperature in the dark. The resultant signals arising from laser light excitation at 680 run were read using a Packard Envision instrument.
Phosphorylated biotinylated peptide is formed in situ as a result of mTOR mediated phosphorylation. The phosphorylated biotinylated peptide that is associated io with AlphaScreen Streptavidin donor beads forms a complex with the p70 S6 Kinase (T389) 1A5 Monoclonal Antibody that is associated with Alphascreen Protein A acceptor beads. Upon laser light excitation at 680 nm, the donor bead : acceptor bead complex produces a signal that can be measured. Accordingly, the presence of mTOR kinase activity results in an assay signal. In the presence of an mTOR kinase inhibitor, signal is strength is reduced. mTOR enzyme inhibition for a given test compound was expressed as an IC50 value, (b) In Vitro PI3K Enzyme Assay
The assay used AlphaScreen technology (Gray et al. , Analytical Biochemistry,
20 2003, 313: 234-245) to determine the ability of test compounds to inhibit phosphorylation by recombinant Type I PI3K enzymes of the lipid PI(4,5)P2.
DNA fragments encoding human PI3K catalytic and regulatory subunits were isolated from cDNA libraries using standard molecular biology and PCR cloning techniques. The selected DNA fragments were used to generate baculovirus expression
25 vectors. In particular, full length DNA of each of the pi 10a, pi lOβ and pi 105 Type Ia human PI3K pi 10 isoforms (EMBL Accession Nos. HSU79143, S67334, Y10055 for pi 10a, pi lOβ and pi 105 respectively) were sub-cloned into a pDESTIO vector (Invitrogen Limited, Fountain Drive, Paisley, UK). The vector is a Gateway-adapted version of Fastbacl containing a 6-His epitope tag. A truncated form of Type Ib human
30 PI3K pi lOγ isoform corresponding to amino acid residues 144-1102 (EMBL Accession No. X8336A) and the full length human p85α regulatory subunit (EMBL Accession No. HSPl 3KIN) were also sub-cloned into pFastBacl vector containing a 6-His epitope tag. The Type Ia pi 10 constructs were co-expressed with the p85α regulatory subunit. Following expression in the baculovirus system using standard baculovirus expression techniques, expressed proteins were purified using the His epitope tag using standard purification techniques. DNA corresponding to amino acids 263 to 380 of human general receptor for phosphoinositides (Grpl) PH domain was isolated from a cDNA library using standard molecular biology and PCR cloning techniques. The resultant DNA fragment was sub- cloned into a pGEX 4Tl E. coli expression vector containing a GST epitope tag (Amersham Pharmacia Biotech, Rainham, Essex, UK) as described by Gray et al, Analytical Biochemistry. 2003, 313.: 234-245). The GST-tagged Grpl PH domain was expressed and purified using standard techniques.
Test compounds were prepared as 10 mM stock solutions in DMSO and diluted into water as required to give a range of final assay concentrations. Aliquots (2 μl) of each compound dilution were placed into a well of a Greiner 384- well low volume (LV) white polystyrene plate (Greiner Bio-one, Brunei Way, Stonehouse, Gloucestershire, UK Catalogue No. 784075). A mixture of each selected recombinant purified PI3K enzyme (15 ng), DiC8-PI(4,5)P2 substrate (40 μM; Cell Signals Inc., Kinnear Road, Columbus, USA, Catalogue No. 901), adenosine triphosphate (ATP; 4 μM) and a buffer solution [comprising Tiϊs-HCl pH7.6 buffer (40 mM, 10 μl), 3-[(3- cholamidopropyl)dimethylammonio]-
1-propanesulfonate (CHAPS; 0.04%), dithiothreitol (DTT; 2 mM) and magnesium chloride (10 mM)] was agitated at room temperature for 20 minutes.
Control wells that produced a minimum signal corresponding to maximum enzyme activity were created by using 5% DMSO instead of test compound. Control wells that produced a maximum signal corresponding to fully inhibited enzyme were created by adding wortmannin (6 μM; Calbiochem / Merck Bioscience, Padge Road, Beeston, Nottingham, UK, Catalogue No. 681675) instead of test compound. These assay solutions were also agitated for 20 minutes at room temperature.
Each reaction was stopped by the addition of 10 μl of a mixture of EDTA (100 mM), bovine serum albumin (BSA, 0.045 %) and Tris-HCl pH7.6 buffer (40 mM). Biotinylated-DiC8-PI(3,4,5)P3 (50 nM; Cell Signals Inc., Catalogue No. 107), recombinant purified GST-Gipl PH protein (2.5 nM) and AlphaScreen Anti-GST donor and acceptor beads (100 ng; Packard Bioscience Limited, Station Road, Pangbourne, Berkshire, UK, Catalogue No. 6760603M) were added and the assay plates were left for about 5 to 20 hours at room temperature in the dark. The resultant signals arising from laser light excitation at 680 run were read using a Packard AlphaQuest instrument.
PI(3,4,5)P3 is formed in situ as a result of PI3K mediated phosphorylation of PI(4,5)P2. The GST-Grpl PH domain protein that is associated with AlphaScreen Anti- GST donor beads forms a complex with the biotinylated PI(3,4,5)P3 that is associated with Alphascreen Streptavidn acceptor beads. The enymatically-produced PI(3,4,5)P3 competes with biotinylated PI(3,4,5)P3 for binding to the PH domain protein. Upon laser light excitation at 680 mil, the donor bead : acceptor bead complex produces a signal that can be measured. Accordingly, PI3K enzme activity to form PI(3,4,5)P3 and subsequent competition with biotinylated PI(3,4,5)P3 results in a reduced signal. In the presence of a PI3K enzyme inhibitor, signal strength is recovered.
PI3K enzyme inhibition for a given test compound was expressed as an IC50 value, (c) In Vitro phospho-Ser473 Akt assay
This assay determines the ability of test compounds to inhibit phosphorylation of Serine 473 in Akt as assessed using Acumen Explorer technology (Acumen Bioscience Limited), a plate reader that can be used to rapidly quantitate features of images generated by laser-scanning.
A MDA-MB-468 human breast adenocarcinoma cell line (LGC Promochem, Teddiiigton, Middlesex, UK, Catalogue No. HTB-132) was routinely maintained at 37°C with 5% CO2 up to a confluency of 70-90% in DMEM containing 10% heat-inactivated FCS and 1% L-glutamine.
For the assay, the cells were detached from the culture flask using "Accutase' (Innovative Cell Technologies Inc., San Diego, CA, USA; Catalogue No. ATI 04) using standard tissue culture methods and resuspended in media to give 1.7xlO5 cells per mL. Aliquots (90 μl) were seeded into each of the inner 60 wells of a black Packard 96 well plate (PerkinElmer, Boston, MA, USA; Catalogue No. 6005182) to give a density of -15000 cells per well. Aliquots (90 μl) of culture media were placed in the outer wells to prevent edge effects. The cells were incubated overnight at 37°C with 5% CO2 to allow them to adhere.
On day 2, the cells were treated with test compounds and incubated for 2 hours at 37°C with 5% CO2. Test compounds were prepared as 10 niM stock solutions in DMSO and serially diluted as required with growth media to give a range of concentrations that were 10-fold the required final test concentrations. Aliquots (10 μl) of each compound dilution were placed in a well (in triplicate) to give the final required concentrations. As a minimum reponse control, each plate contained wells having a final concentration of 100 μM LY294002 (Calbiochem, Beeston, UK, Catalogue No. 440202). As a maximum response control, wells contained 1% DMSO instead of test compound. Following incubation, the contents of the plates were fixed by treatment with a 1.6% aqueous formaldehyde solution (Sigma, Poole, Dorset, UK, Catalogue No. F 1635) at room temperature for 1 hour.
All subsequent aspiration and wash steps were carried out using a Tecan 96 well plate washer (aspiration speed 10 mm/sec). The fixing solution was removed and the contents of the plates were washed with phosphate-buffered saline (PBS; 50 μl; Gibco, Catalogue No. 10010015). The contents of the plates were treated for 10 minutes at room temperature with an aliquot (50 μl) of a cell pemieabilisation buffer consisting of a mixture of PBS and 0.5% Tween-20. The 'permeabilisation' buffer was removed and non-specific binding sites were blocked by treatment for 1 hour at room temperature of an aliquot (50 μl) of a blocking buffer consisting of 5% dried skimmed milk ['Marvel' (registered trade mark); Premier Beverages, Stafford, GB] in a mixture of PBS and 0.05% Tween-20. The 'blocking' buffer was removed and the cells were incubated for 1 hour at room temperature with rabbit anti phospho-Akt (Ser473) antibody solution (50 μl per well; Cell Signalling, Hitchin, Herts, U.K., Catalogue No 9277) that had been diluted 1 :500 in 'blocking' buffer. Cells were washed three times in a mixture of PBS and 0.05% Tween-20. Subsequently, cells were incubated for 1 hour at room temperature with Alexafluor488 labelled goat anti-rabbit IgG (50 μl per well; Molecular Probes, Invitrogen Limited, Paisley, UK, Catalogue No. Al 1008) that had been diluted 1 :500 in 'blocking' buffer. Cells were washed 3 times with a mixture of PBS and 0.05% Tween-20. An aliquot of PBS (50 μl) was added to each well and the plates were sealed with black plate sealers and the fluorescence signal was detected and analysed.
Fluorescence dose response data obtained with each compound were analysed and the degree of inhibition of Serine 473 in Akt was expressed as an IC5O value. (d) In Vitro MDA-MB-468 human breast adenocarcinoma Proliferation Assay
This assay determines the ability of test compounds to inhibit cell proliferation as assessed using Cellomics Array scan technology. A MDA-MB-468 human breast adenocarcinoma cell line (LGC Promochem, Catalogue No. HTB- 132) was routinely maintained as described in Biological Assay (b) herein. For the proliferation assay, the cells were detached from the culture flask using
Accutase and seeded into the inner 60 wells of a black Packard 96 well plate at a density of 8000 cells per well in 100 μl of complete growth media. The outer wells contained 100 μl of sterile PBS. The cells were incubated overnight at 37°C with 5% CO2 to allow them to adhere. On day 2, the cells were treated with test compounds and incubated for 48 hours at
37°C with 5% CO2. Test compounds were prepared as 10 mM stock solutions in DMSO and serially diluted as required with growth media to give a range of test concentrations. Aliquots (50 μl) of each compound dilution were placed in a well and the cells were incubated for 2 days at 370C with 5% CO2. Each plate contained control wells without test compound.
On day 4, BrdU labelling reagent (Sigma, Catalogue No. B9285) at a final dilution of 1 :1000 was added and the cells were incubated for 2 hours at 37°C. The medium was removed and the cells in each well were fixed by treatment with 100 μl of a mixture of ethanol and glacial acetic acid (90% ethanol, 5% glacial acetic acid and 5% water) for 30 minutes at room temperature. The cells in each well were washed twice with PBS (100 μl). Aqueous hydrochloric acid (2M, 100 μl) was added to each well. After 20 minutes at room temperature, the cells were washed twice with PBS. Hydrogen peroxide (3%, 50 μl; Sigma, Catalogue No. H1009) was added to each well. After 10 minutes at room temperature, the wells were washed again with PBS. BrdU incorporation was detected by incubation for 1 hour at room temperature with mouse anti-BrdU antibody (50 μl; Caltag, Burlingame, CA, US; Catalogue No. MD5200) that was diluted 1:40 in PBS containing 1% BSA and 0.05% Tween-20. Unbound antibody was removed with two washes of PBS. For visualisation of incorporated BrdU, the cells were treated for 1 hour at room temperature with PBS (50 μl) and 0.05% Tween-20 buffer containing a 1 :1000 dilution of Alexa fluor 488-labelled goat anti-mouse IgG. For visualisation of the cell nucleus, a 1 :1000 dilution of Hoechst stain (Molecular Probes, Catalogue No. H3570) was added. Each plate was washed in turn with PBS. Subsequently, PBS (100 μl) was added to each well and the plates were analysed using a Cellomics array scan to assess total cell number and number of BrdU positive cells. Fluorescence dose response data obtained with each compound were analysed and the degree of inhibition of MDA-MB-468 cell growth was expressed as an IC5Q value. Although the pharmacological properties of the compounds of formula (I) vary with structural change as expected, in general, it is believed that activity possessed by compounds of formula (I) may be demonstrated at the following concentrations or doses in one or more of the above tests (a) to (d) :-
Test (a):- IC50 versus mTOR kinase at less than 10 μM, in particular less than 5 μM for many compounds, for Example 4 the IC50 was measured on three occasions, the values were 3.32, 2.49 and 2.25μM; Test (b):- IC50 versus pi lOγ Type Ib human PI3K at less than 10 μM; and IC50 versus pi 10a Type Ia human PI3K at less than 10 μM; For
Example 4 the ICs0 was measured on three occasions, the values were >134, 54, >698 μM, indicating this compound may be a selective mTOR inhibitor;
Test (c):- IC50 versus Serine 473 in Akt at less than 100 μM, in particular less than 35 μM for many compounds, for Example 4 the IC50 was measured on three occasions, the values were 11.29, 24.05 and >31.88 μM;
Test (d):- IC50 at less than 20 μM;
The compounds of the present invention are advantageous in that they possess pharmacological activity. In particular, the compounds of the present invention modulate (in particular, inhibit) mTOR kinase and/or phosphatidylinositol-3 -kinase (PI3K) enzymes, such as the Class Ia PI3K enzymes (e.g. PBKalpha, PDKbeta and POKdelta) and the Class Ib PBK enzyme (PBKgamma). More particularly compounds of the present invention modulate (in particular, inhibit) mTOR kinase. More particularly compounds of the present invention modulate (in particular, inhibit) one or more PI3K enzyme. The inhibitory properties of compounds of formula (I) may be demonstrated using the test procedures set out herein and in the experimental section. Accordingly, the compounds of formula (I) may be used in the treatment (therapeutic or prophylactic) of conditions/diseases in human and non-human animals which are mediated by mTOR ldnase and/or one or more PD K enzyme(s), and in particular by mTOR kinase.
The invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in association with a pharmaceutically acceptable diluent or carrier.
The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).
The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents. The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 1 mg to 1 g of active agent (more suitably from 1 to 250 mg, for example from 1 to 100 mg) compounded with an appropriate and convenient amount of excipients which may vaiy from about 5 to about 98 percent by weight of the total composition.
The size of the dose for therapeutic or prophylactic purposes of a compound of formula I will naturally vaiy according to the nature and severity of the disease state, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
In using a compound of formula (I) for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 1 mg/kg to 100 mg/kg body weight is received, given if required in divided doses. In general, lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, 1 mg/kg to 25 mg/kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 1 mg/kg to 25 mg/kg body weight will be used. Typically, unit dosage forms will contain about 10 mg to 0.5 g of a compound of this invention.
As stated herein, it is known that mTOR kinase and the PI 3 K enzymes have roles in tumourigenesis as well as numerous other diseases. We have found that the compounds of formula (I) possess potent anti-tumour activity which it is believed is obtained by way of inhibition of mTOR kinase and/or one or more of the PBK enzymes.
Accordingly, the compounds of the present invention are of value as anti-tumour agents. Particularly, the compounds of the present invention are of value as antiproliferative, apoptotic and/or anti-invasive agents in the containment and/or treatment of solid and/or liquid tumour disease. Particularly, the compounds of the present invention are expected to be useful in the prevention or treatment of those tumours which are sensitive to inhibition of mTOR and/or one or more of the PI3K enzymes such as the Class Ia PI3K enzymes and the Class Ib PI3K enzyme. Further, the compounds of the present invention are expected to be useful in the prevention or treatment of those tumours which are mediated alone or in part by mTOR and/or one or more of the PI3K enzymes such as the Class Ia PI3K enzymes and the Class Ib PI3K enzyme. The compounds may thus be used to produce an mTOR enzyme inhibitory effect in a warm-blooded animal in need of such treatment. Certain compounds may be used to produce an PI3K enzyme inhibitory effect in a warm-blooded animal in need of such treatment.
As stated herein, inhibitors of mTOR kinase and/or one or more PI3K enzymes should be of therapeutic value for the treatment of proliferative disease such as cancer and in particular solid tumours such as carcinoma and sarcomas and the leukaemias and lymphoid malignancies and in particular for treatment of, for example, cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate, and of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias [including acute lyniphoctic leukaemia (ALL) and chronic myelogenous leukaemia (CML)], multiple myeloma and lymphomas.
According to a further aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein for use as a medicament in a warm-blooded animal such as man. According to a further aspect of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein for use in the production of an antiproliferative effect in a warm-blooded animal such as man.
According to a further aspect of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein for use in the production of an apoptotic effect in a warm-blooded animal such as man.
According to a further feature of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein for use in a warm-blooded animal such as man as an anti-invasive agent in the containment and/or treatment of proliferative disease such as cancer. According to a further aspect of the invention, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein for the production of an antiproliferative effect in a warm-blooded animal such as man. According to a further feature of this aspect of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the production of an antiproliferative effect in a warm-blooded animal such as man.
According to a further aspect of the invention, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein for the production of an apoptotic effect in a warm-blooded animal such as man. According to a further feature of this aspect of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the production of an apoptotic effect in a warm-blooded animal such as man.
According to a further feature of the invention there is provided the use of a compound of formula (I)5 or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in a warm-blooded animal such as man as an anti-invasive agent in the containment and/or treatment of proliferative disease such as cancer.
According to a further feature of this aspect of the invention there is provided a method for producing an antiproliferative effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein.
According to a further feature of this aspect of the invention there is provided a method for producing an anti-invasive effect by the containment and/or treatment of solid tumour disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein.
According to a further aspect of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the prevention or treatment of proliferative disease such as cancer in a warm-blooded animal such as man.
According to a further feature of this aspect of the invention there is provided a method for the prevention or treatment of proliferative disease such as cancer in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein.
According to a further aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein for use in the prevention or treatment of those tumours which are sensitive to inhibition of mTOR kinase and/or one or more PDK enzymes (such as the Class Ia enzymes and/or the Class Ib PI3K enzyme) that are involved in the signal transduction steps which lead to the proliferation, survival, invasiveness and migratory ability of tumour cells. According to a further feature of this aspect of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the prevention or treatment of those tumours which are sensitive to inhibition of mTOR kinase and/or one or more POK enzymes (such as the Class Ia enzymes and/or the Class Ib PI3K enzyme) that are involved in the signal transduction steps which lead to the proliferation, survival, invasiveness and migratoiy ability of tumour cells.
According to a further feature of this aspect of the invention there is provided a method for the prevention or treatment of those tumours which are sensitive to inhibition of mTOR kinase and/or one or more PI3K enzymes (such as the Class Ia enzymes and/or the Class Ib PI3K enzyme) that are involved in the signal transduction steps which lead to the proliferation, survival, invasiveness and migratoiy ability of tumour cells which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein. According to a further aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein for use in providing a mTOR kinase inhibitory effect and/or a PI3K enzyme inhibitory effect (such as a Class Ia PI3K enzyme or Class Ib PI3K enzyme inhibitory effect).
According to a further feature of this aspect of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in providing a mTOR kinase inhibitory effect and/or a PI3K enzyme inhibitory effect (such as a Class Ia PI3K enzyme or Class Ib PI3K enzyme inhibitory effect).
According to a further aspect of the invention there is also provided a method for providing a mTOR kinase inhibitory effect and/or a PI3K enzyme inhibitory effect (such as a Class Ia PI3K enzyme or Class Ib PI3K enzyme inhibitory effect) which comprises administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, as defined herein.
According to a further feature of the invention there is provided a compound of formula I, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of cancer, inflammatory diseases, obstructive airways diseases, immune diseases or cardiovascular diseases. According to a further feature of the invention there is provided a compound of formula I5 or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of solid tumours such as carcinoma and sarcomas and the leukaemias and lymphoid malignancies. According to a further feature of the invention there is provided a compound of formula I5 or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of cancer of the breast, colorectum, lung (including small cell lung cancer, non- small cell lung cancer and bronchioalveolar cancer) and prostate.
According to a further feature of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas. According to a further feature of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the treatment of cancer, inflammatory diseases, obstructive airways diseases, immune diseases or cardiovascular diseases. According to a further feature of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the treatment of of solid tumours such as carcinoma and sarcomas and the leukaemias and lymphoid malignancies.
According to a further feature of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the treatment of cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate.
According to a further feature of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the treatment of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas.
According to a further feature of the invention there is provided a method for treating cancer, inflammatory diseases, obstructive airways diseases, immune diseases or cardiovascular diseases in a warm blooded animal such as man that is in need of such treatment which comprises administering an effective amount of a compound of formula
(I), or a pharmaceutically acceptable salt thereof, as defined herein.
According to a further feature of the invention there is provided a method for treating solid tumours such as carcinoma and sarcomas and the leukaemias and lymphoid malignancies in a warm blooded animal such as man that is in need of such treatment which comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein.
According to a further feature of the invention there is provided a method for treating cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate in a warm blooded animal such as man that is in need of such treatment which comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein.
According to a further feature of the invention there is provided a method for treating cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas in a warm blooded animal such as man that is in need of such treatment which comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein.
As stated herein, the in vivo effects of a compound of formula (I) may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of formula (I).
The invention further relates to combination therapies wherein a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound of formula (I) is administered concurrently or sequentially or as a combined preparation with another treatment of use in the control of oncology disease.
In particular, the treatment defined herein may be applied as a sole therapy or may involve, in addition to the compounds of the invention, conventional surgery or radiotherapy or chemotherapy. Accordingly, the compounds of the invention can also be used in combination with existing therapeutic agents for the treatment of cancer.
Suitable agents to be used in combination include :-
(i) antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea and gemcitabine); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like paclitaxel and taxotere); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecins); (ii) cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5α-reductase such as finasteride;
(iii) anti-invasion agents (for example c-Src kinase family inhibitors like 4-(6-chloro- 2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-l-yl)ethoxy]-5-tetrahydropyran- 4-yloxyquinazoline (AZD0530; International Patent Application WO 01/94341) and N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-l-yl]-2- methylpyrimidin-
4-ylamino}thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem.. 2004, 47, 6658-6661), and metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function);
(iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [Herceptin™] and the anti-erbBl antibody cetuximab [C225]); such inhibitors also include, for example, tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as
N-(3-chloiO-4-fluoiOphenyl)-7-methoxy-6-(3-morpholinopiOpoxy)quinazolin-4-amine (gefitinib, ZDl 839), N-(3-ethynylphenyl)-657-bis(2-methoxyethoxy)quinazolin-4-amine
(erlotinib, OSI-774) and 6-aciylamido-N-(3-chloro-4-fluorophenyl)-7-(3- morpholinopropoxy)quinazolin-4-amine (CI 1033) and erbB2 tyrosine kinase inhibitors such as lapatinib), inhibitors of the hepatocyte growth factor family, inhibitors of the platelet-derived growth factor family such as imatinib, inhibitors of serine/threonine kinases (for example Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006)) and inhibitors of cell signalling through MEK and/or Akt kinases;
(v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin™) and VEGF receptor tyrosine kinase inhibitors such as
4-(4-biOmo-2-fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline
(ZD6474;
Example 2 within WO 01/32651), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-
7-(3-pyrrolidin-l-ylpropoxy)quinazoline (AZD2171; Example 240 within WO 00/47212), vatalanib (PTK787; WO 98/35985) and SUl 1248 (sunitinib; WO 01/60814), and compounds that work by other mechanisms (for example linomide, inhibitors of integrin αvβ3 function and angiostatin)];
(vi) vascular damaging agents such as combretastatin A4 and compounds disclosed in
International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
(vii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense agent; (viii) gene therapy approaches, including approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and (ix) immunotherapeutic approaches, including ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
The invention will now be further explained by reference to the following illustrative examples.
Unless stated otherwise, starting materials were commercially available. All solvents and commercial reagents were of laboratory grade and were used as received.
In the examples 1H NMR spectra were recorded on a Bruker DPX 300 (300 MHz), Bruker DRX 400 (400 MHz) instrument or a Bruker DRX 500 (500 MHz) instrument. The central peaks of chloroform-d (6H 7.27 ppm), dimethylsulfoxide-d6 (5H 2.50 ppm) or acetone-d6 (δπ 2.05 ppm) were used as internal references. The following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.
Column chromatography was earned out using silica gel (0.04-0.063 mm, Merck). In general, a Kromasil KR-100-5-C18 reversed-phase column (250 x 20 mm, Akzo Nobel) was used for preparative HPLC with mixtures of acetonitrile and water [containing 0.1% trifluoroacetic acid (TFA)] used as the eluent at a flow rate of 10 mL/min.
The following methods were used for liquid chromatography (LC) / mass spectral (MS) analysis :-
HPLC: Agilent 1100 or Waters Alliance HT (2790 & 2795)
Mass Spectrometer: Waters ZQ ESCi HPLC Column
The standard HPLC column used is the Phemonenex Gemini Cl 8 5μm, 50 x 2 mm. Acidic HPLC Methods
The mobile phases used are: Mobile phase A: Water
Mobile Phase B: Acetonitrile
Mobile Phase C: 1% Formic Acid in 50:50 Water :MeCN
Figure imgf000089_0001
Each method is followed by a rapid equilibration using a 5 mL flow rate for 0.45 min.
Four generic HPLC methods are available: 5 Minute Monitor Acidic method
Figure imgf000089_0002
Early Acidic method for early eluting compounds
Figure imgf000089_0003
Mid Acidic method for middle eluting compounds
Figure imgf000089_0004
Late Acidic method for late eluting compounds
Figure imgf000090_0001
Basic HPLC methods
In some instances the standard acidic methods may be unsuitable for either the compound ioiiisation or the chromatography separation required. In such cases four comparable Basic HPLC methods are available. The mobile phases used are: Mobile phase A: Water
Mobile Phase B: Acetonitrile
Mobile Phase D: 0.1% 880 Ammonia in acetonitrile Each method is followed by a rapid equilibration using a 5 mL flow rate for 0.45 min. Minute Monitor Basic method
Figure imgf000090_0002
Earlv Basic method for early eluting compounds
Figure imgf000091_0001
Mid Basic method for middle eluting compounds
Figure imgf000091_0002
Late Basic method for late eluting compounds
Figure imgf000091_0003
The following method was used for liquid chromatography (LC) / mass spectral (MS) analysis :-
Instrument: Agilent 1100; Column: Waters 'Symmetry' 2.1 x 30 mm; Mass Spectral analysis using chemical ionisation (APCI); Flow rate: 0.7 mL/min; Absorption
Wavelength: 254 nm; Solvent A: water + 0.1% TFA; Solvent B: acetonitrile + 0.1% TFA ; Solvent Gradient: 15-95% Solvent B for 2.7 minutes followed by 95% Solvent B for 0.3 minutes. The following methods were used for LC analysis :-
Method A :- Instrument: Agilent 1100; Column: Kromasil Cl 8 reversed-phase silica, 100 x 3 mm, 5μm particle size; Solvent A: 0.1% TF A/water, Solvent B: 0.08%
TFA/acetonitrile; Flow Rate: 1 mL/min; Solvent Gradient: 10-100% Solvent B for 20 minutes followed by 100% Solvent B for 1 minute; Absorption Wavelengths: 220, 254 and 280 nm. In general, the retention time of the product was noted.
Method B :- Instrument: Agilent 1100; Column: Waters 'Xterra' C8 reversed- phase silica, 100 x 3 mm, 5μm particle size; Solvent A: 0.015M ammonia in water,
Solvent B: acetonitrile; Flow Rate: 1 ml/min, Solvent Gradient: 10-100% Solvent B for 20 minutes followed by 100% Solvent B for 1 minute; Absorption Wavelength: 220, 254 and
280 nm. In general, the retention time of the product was noted.
The following abbreviations are used herein or within the following illustrative examples :-
HPLC High Performance Liquid Chromatography HBTU O-(benzotriazol-l-yl)-iV,A^,N',^/-tetramethyluronium hexafluorophosphate;
HATU 0-(7-azabenzotriazol- 1 -yl)-7V,N,N',N'-tetramethyluronium hexafluorophosphate;
HOBT 1-hydroxybenzotriazole;
HOAT 1 -hydroxy-7-azabenzotriazole;
NMP iV-methylpyrrolidin-2-one; 0 DMSO dimethylsulfoxide;
DMF N,iV-dimethylformamide;
DMA iVjiV-dimethylacetamide;
THF tetrahydrofuran;
DME 1,2-dimethoxyethane; s DCCI dicyclohexylcarbodiimide;
MeOH methanol;
MeCN acetonitrile;
DCM dichloromethane;
DIPEA N,iV-diisopropylethylamine; 0 DBU l,8-diazabicyclo[5.4.0]undec-7-ene;
RT room temperature (approximately 17 to 250C); tR retention time; m/z mass/charge ratio.
The chemical names were generated by software which used the Lexichem Toolkit (v. 1.40) from OpenEye Scientific Software (www.eyesopen.com) to generate IUPAC conforming names.
5
Example 1: Λ/-[2-(Hvdroxymethvπ-4-[4-(methylsulfonylmethyI)-6-tnorpholin-4-yl- Pyrimidin-2-yllphenyllmethanesulfonamide
Figure imgf000093_0001
A mixture of Λ^-[4-bromo-2-(hydiOxymethyl)phenyl]methanesulfonamide (250 mg), io potassium acetate (263 mg) and bis(pinacolato)diboron (273 mg) in 1,4-dioxane (10 mL) was degassed for 5 minutes. l,r-Bis(diplienylphosphino)feiτocenedichloropalladium(II) dichloromethane adduct (44 mg) was added and the reaction was heated to 8O0C for 3 hours. 2-Chloro-4-(methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidine (261 mg), ethanol (0.75 mL), a 2M solution of sodium carbonate (2.7 mL) and additional 1,1'-
I5 bis(diphenylphosphino)fenOcenedichloropalladium(II) dichloromethane adduct (54 mg) were added and the heating was continued for a further 3 hours. The cooled reaction mixture was concentrated in vacuo, dissolved in methanol and loaded onto a SCX-2 column. The column was washed with methanol and the compound removed with 7N ammonia in methanol. The solution was concentrated in vacuo and the residue
20 chromatographed on silica, eluting with 0-5% methanol in DCM. The resulting solid was triturated with diethyl ether to give the desired material as a white solid (62 mg). NMR Spectrum; 1H NMR (DMSO-d6) 53.07 (3H, s), 3.22 (3H, s), 3.74 (8H, s), 4.53 (2H, s), 4.69 (2H, s), 5.44 (IH, s), 6.89 (IH, s), 7.45 (IH, d), 8.23 - 8.26 (IH, m), 8.43 (IH, s), 9.1O (1H, s)
25 Mass Spectrum; M+H+ 457. Test (a) average IC50 5μM. The preparation of ΛL[4-biOmo-2-(hydiOxymethyl)phenyl]methanesulfonamide is described below:
A^4-bromo-2-('hvdroxymethyl)phenyl1methanesulfonamide
Figure imgf000094_0001
Methyl 5-biOmo-2-methanesulfonamido-benzoate (1.34 g) was dissolved in THF (30 niL) and cooled to O0C. Lithium aluminium hydride (8.7 niL, IM solution THF) was added slowly to the solution over 15 minutes. The reaction was allowed to warm to room temperature and stir for 2 hours before being quenched with water and filtered. The solution was concentrated in vacuo and the residue chromatographed on silica, eluting with 2.5% methanol in DCM, to give the desired material as a white solid (333 mg). NMR Spectrum: 1H NMR (DMSOd6) 53.01 (3H, s), 4.61 (2H, s), 5.40 (IH, s), 7.26 (IH5 d), 7.45 - 7.48 (IH, m), 7.62 (IH, d), 9.05 - 9.05 (IH, m) Mass Spectrum; M-H+ 280.
Methyl 5-biOmo-2-methanesulfonamido-benzoate
Figure imgf000094_0002
Sodium borohydride (659 mg) was added portion wise to a stirred solution of methyl 2- (bis(methylsulfonyl)amino)-5-bromo-benzoate (1.68 g) in methanol (40 niL) and water (4 mL) at O0C. The reaction was allowed to waπn to room temperature and left to stir for 2 hours. Other portion of sodium borohydride was added at O0C and was left to stir for 18h. Water (10 mL) and Sodium carbonate (2M) (5 mL) was added to quench the reaction. The reaction was vacuumed to dryness and partitioned between ethyl acetate (50 mL) and water (50 mL). Organics dried over magnesium sulphate, filtered and vacuumed to dryness to give the desired material as a white solid (1.34 g). NMR Spectrum: 1H NMR (DMSO-d6) 53.14 (3H, d), 3.89 (3H, s), 7.52 - 7.57 (IH, m), 7.78 - 7.81 (IH, m), 7.99 (IH, d) Mass Spectrum; M-H+ 306.
s Methyl 2-('bis(methylsulfonyl)amino)-5-biOmo-benzoate
Figure imgf000095_0001
Methyl-2-amino-5-bromobenzoate (1 g) was dissolved in THF (20 mL) and triethylamine (3.6 mL). The mixture was cooled to O0C in an ice bath and methanesulfonyl chloride (1 mL) was added slowly. The reaction was allowed to stir at O0C for 15 minutes then left too stir for 19 hours at room temperature. The reaction was quenched with water (10 mL) and concentrated in vacuo. The reaction was partitioned between ethyl acetate (50 mL) and water (50 mL), the organics dried (MgSO4), filtered, and concentrated in vacuo to give the desired material (1.68 g) as a white solid. NMR Spectrum: 1H NMR (DMSOd6) 53.52 (6H, s), 3.87 (3H, s), 7.58 (IH, d), 7.94 -s 7.97 (IH, m), 8.10 (IH, d) Mass Spectrum: M+H+ 386.
The preparation of 2-Chloro-4-(methylsulfonylmethyl)-6-morpholin-4-yl-pyriniidine is described below. 0
2-ChloiO-4-(methylsulfonylmethyl)-6-morpholin-4-yl-pyriniidine
Figure imgf000095_0002
A suspension of 2,4-dichloiO-6-(metliylsulfonylmethyl)pyiϊmidine (10.56 g) in DCM (230 mL) was stirred magnetically (under nitrogen) and cooled to -50C. Triethylamine (6.785 mL) was added followed by the dropwise addition of a solution of morpholine (3.85 mL) in DCM (30 mL) maintaining the reaction temperature below -50C. The reaction was stirred at room temperature for 1 hour and then the organic mixture washed with water (300 mL). The organic phase was dried ( MgSO4), filtered and evaporated to a brown solid which was chromatographed on silica, eluting with 50% ethyl acetate in DCM, to give the desired material (6.8Ig) as a white solid. NMR Spectrum: 1H NMR (DMSOd6) 53.12 (3H, s), 3.63 (4H, s), 3.68 - 3.70 (4H, m), 4.45 (2H, s), 6.96 (IH, s) Mass Spectrum: MH+ 292.
2,4-DichloiO-6-(methylsulfonylmethyl)pyiϊmidiiie
Figure imgf000096_0001
6-(Methylsulfonylmethyl)-lff-pyrimidine-2,4-dione (12.72 g) was suspended in phosphorus oxy chloride (125 mL) and heated at reflux under nitrogen for 14 hours. The solution was cooled and concentrated in vacuo to. Iced water (250 mL) was slowly added to the residue and the product then extracted with DCM (3 x 200 mL). The organics were concentrated in vacuo to give the desired material as a brown solid (10.56 g). NMR Spectrum: 1H NMR (DMSOd6) 63.14 (3H, s), 4.79 (2H, s), 7.88 (IH, s) Mass Spectrum: (M-H)" 239.
6-(MethylsulfonymiethylMH-pyrimidine-2,4-dione
Figure imgf000096_0002
6-(Chloromethyl)uracil (10.00 g) was dissolved in DMF (300 mL) and methanesulphinic acid sodium salt (7.64 g) added. The reaction was heated at 1250C for 1 hour. The reaction was allowed to cool, filtered and the filtrate concentrated in vacuo to give the desired material as a yellow solid (12.72 g). NMR Spectrum: 1H NMR (DMSOd6) 63.10 (3H, s), 4.27 (2H, s), 5.63 (IH, s), 10.94 (IH, s), 11.16 (IH, s). Example 2: iV-[[4-[4-(Methylsulfonylmethvπ-6-morphoIin-4-yl-pyπmidin-2- yllphenyll methyl! methanesulfonamide
Figure imgf000097_0001
[4-[4-(Methylsulfonylmethyl)-6-moipholin-4-yl-pyrimidin-2-yl]phenyl]methanamine (72 mg) was suspended in DCM (4 niL) and treated with tiϊethylamine (0.056 mL). Methane sulfonyl chloride (0.024 mL) was then added dropwise and the reaction stirred overnight at RT. The reaction was quenched by the addition of water (2 mL) and the layers were separated. The aqueous layer was extracted with DCM (2 x 2 mL) and the combined organics were dried, filtered and evaporated to a green oil which was purified on the basic prep HPLC system. The product containing fractions were loaded onto a methanol pre- eluted SCX column, washed with methanol, then eluted with 7N ammonia in methanol.
The desired fractions were evaporated in vacuo, to give the desired material as a white solid (20 mg).
LCMS Spectrum: MH+ 441.58, Retention Time 1.41 Method: Monitor Acid NMR Spectrum: 1H NMR (300.132 MHz, DMSO-d6) 62.89 (s, 3H), 3.20 (s, 3H), 3.71 (s,
8H), 4.25 (d, 2H), 4.51 (s, 2H), 6.91 (s, IH), 7.45 (m, 2H), 7.62 (m, IH), 8.34 (m, 2H).
Test (a) average IC50 6.8μM.
The starting material [4-[4-(methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidin-2- yl]phenyl]methanamine was prepared as follows. r4-r4-(Methylsulfonylmethyl)-6-moφholin-4-yl-pyrimidin-2-yllphenyl]methananiine
Figure imgf000098_0001
2-Methylsulfanyl-4-(methylsulfonylmethyl)-6-moipholin-4-yl-pyrimidine (228 mg), [4-
(aminomethyl)phenyl]boiOnic acid (310 mg), Copper(I)thiophene-2-carboxylate (373 mg) and Pd(PPh3)4 (35 mg) were added to a microwave vessel and 1, 4-Dioxane (5 mL) was then added. The system was sealed and heated in a microwave reactor at 13O0C for 1 hour.
Further Pd(PPh3 )4 (10 mg) was added and the reaction heated to 130°C for 20 minutes.
The mixture was transferred to an SCX column, previously eluted with methanol. The
SCX column was then flushed with methanol before the desired material was eluted with 7N ammonia in methanol. The fractions were evaporated to give the desired compound as a cream solid (129 mg).
LCMS Spectrum: MH+ 363.55, Retention Time 0.83 Method: Monitor acid
2-Methylsulfanyl-4-(methylsulfonylniethyl)-6-moφholin-4-yl-pyrimidine
Figure imgf000098_0002
2-Methylsulfanyl-6-(methylsulfonylmethyl)pyrimidin-4-ol (15 g, 63.97 mmol) was heated at reflux in phosphorous oxy chloride (100 ml) for approximately 1 hour. Phosphorous oxychloride was evaporated and the residue was neutralised with sodium hydroxide solution and extracted into ethyl acetate. The resultant mixture was then dried over magnesium sulfate, filtered and evaporated to dryness to afford the crude chloro product. This was then dissolved in DCM, morpholine (319 mmol, 28 ml) was added and the reaction stirred at room temperature. Upon completion the resulting precipitate was collected as a white solid. Concentration of the filtrate afforded more solid, giving a combined yield of 13.7g. NMR Spectrum: 1H NMR (300.132 MHz, DMSO) 62.45 (s, 3H)5 3.49 - 3.74 (m, 8H), 4.37
(s, 2H), 6.66 (s, IH) ppm.
LCMS Spectrum: MH+ 304.50, Retention Time 1.49min, Method : Monitor Basic
2-Methylsulfanyl-6-(methylsulfonylmethyl)pyrimidin-4-ol
Figure imgf000099_0001
6-(ChloiOmethyl)-2-methylsulfanyl-pyπmidin-4-ol (19.07 g, 100 mmol) was suspended in acetonitrile (400 ml). To this stirring suspension was added methanesulphinic acid sodium salt (12.255g, 120 mmol) and DMF (100 ml). The reaction was then heated to 100° C to give a dark suspension and monitored by LCMS. Once complete, the solvents were removed and the resultant product added to 1 : 1 MeOH:DCM (200 ml) and acidified with acetic acid (10 ml). The resultant precipitate was collected, washed with water (200 ml) and MeOH (100 ml) and dried overnight in vacuo to afford the title compound as a white solid, 16.45g. NMR Spectrum: 1H NMR (300.132 MHz, DMSO) 52.50 (s, 3H), 3.12 (s, 3H), 4.39 (s, 2H), 6.25 (s, IH), 13.09 (s, IH) ppm. LCMS Spectrum: MH+ 235.2, Retention Time 0.5 minutes, Method: 5min Early Base
6-(Chloromethyl)-2-methylsulfanyl-pyrimidin-4-ol
Figure imgf000099_0002
S-Methyl-2-thiopseudourea sulphate (20 g, 71.85 mmol), ethyl 4-chloroacetoacetate (10.755 ml, 79.04 mmol) and sodium carbonate (13.925 g, 107.78 mmol) were dissolved in water (100 ml) and stirred at room temperature overnight. The reaction was monitored by TLC, and once complete, the reaction precipitate was collected and the supernatant was neutralised with 6N hydrochloric acid to yield more reaction precipitate which was also collected. The accumulated precipitate was then washed with water (x3) and an off-white solid was obtained. This was dried in vacuo at 60° C for 48 hours to yield the desired compound as a pale yellow/white solid, 43.2g. NMR Spectrum: 1H NMR (300.132 MHz, CDCl3) 52.59 (s, 3H), 4.35 (s, 2H), 6.41 (s, IH), 12.70 (s, IH) ppm Mass Spectrum: M+ 190
Example 3; N-[444-(MethylsulfonylmethylV6-morpholin-4-yl-pyrimidin-2- yllpheiiyllcvclopropanesulfonamide
Figure imgf000100_0001
To 4-[4-(methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]aniline (52 mg) in pyridine (4 mL) was added cyclopropane sulphonyl chloride (53 mg) and the reaction was stirred at RT overnight. To the reaction mixture was then added PS-trisamine resin (200 mg) and the mixture was shaken for 2 hours, then filtered and washed with methanol. The combined organics were evaporated to dryness and then dissolved in DMSO (1 mL) and purified by prep HPLC using a Phenomenex 'Gemini' preparative reversed-phase column (5 microns silica, 21.2 mm diameter, 100 mm length) using decreasingly polar mixtures of water and acetonitrile (containing 2% formic acid) as eluent, to yield the title compound. (33 mg).
LCMS Spectrum: M+H+ 453.45; Retention Time 2.59 Method: Monitor Acid Test (a) average IC50 0.88μM.
The following compounds were prepared in an analogous manner to using the appropriate sulphonyl chloride.
Figure imgf000101_0001
Example 3a: Test (a) average IC50 1.4μM. Example 3b: Test (a) average IC50 4μM. Example 3c: Test (a) average IC50 6μM. Example 3d: Test (a) average IC50 7.1μM.
The preparation of 4-[4-(methy lsulfonylmethy l)-6-morpholin-4-y l-pyrimidin-2-y ljaniline is described below: 4-[4-(Methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidin-2-yllaniline
Figure imgf000102_0001
2-Methylsulfanyl-4-(methylsulfoiiylmethyl)-6-moi-pholin-4-yl-pyrimidine (1.0Og, 3.3 niniol), 4-aminophenylboronic acid (904 mg, 6.60 mmol), Copper(I)thiophene-2- carboxylate (1.64 g, 8.58 niniol), Pd(PPh3)4 (153 mg, 0.04 equiv., 0.13 mmol) were added to a microwave vessel and 1 , 4-Dioxane (20 niL) added. The system was degassed with N2, sealed and heated in a microwave reactor at 130° C for 1 hour. Upon cooling the reaction was poured into water and the resulting precipitate was collected by filtration and dried under vacuum to afford the title compound as an off-white solid. (988 mg) LCMS Spectrum: MH+ 349.41, Retention Time 1.43 Method: Monitor Acid
NMR Spectrum: 1H NMR (300.132 MHz, DMSOd6) 53.20 (3H, s), 3.61 - 3.83 (8H, m), 4.43 (2H, s), 5.57 (IH, s), 6.60 (2H, d), 6.70 (IH, s), 8.04 (2H, d)
Example 4: ΛM4-[4-(Methylsulfonylmethv0-6-morpholin-4-yl-pyrimidin-2- vU phenyll methanesulfonamide
Figure imgf000102_0002
To 4-[4-(methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]aniline (53 mg, 0.15 mmol)) in pyridine (3 mL) was added methanesulphonyl chloride (21 mg, 0.18 mmol) and the reaction was stirred at RT for 2 hours. Water (10 mL) was added to the mixture and the precipitate collected by filtration. This solid was purified by prep HPLC to yield the desired material as a white solid (29 mg).
LCMS Spectrum: M+H+ 427.4; Retention Time 1.38 Method: Monitor Acid NMR Spectrum: 1H NMR (300.132 MHz, DMSO-d6) 53.08 (3H, s), 3.22 (3H, s), 3.75 (8H, s), 4.57 (2H, s), 6.93 (IH, s), 7.33 (2H, d), 8.30 (2H, d), 10.12 (IH, s) Test (a) average IC50 2.6μM.
Example 5; JV-ff4-r4-[(3S)-3-Methylmorpholin-4-vIl-6- (methylsulfonylmethvnpyrimidin-2-yllphenyllinethvnmethanesuIfonainide
Figure imgf000103_0001
Triethylamine (0.038 mL, 0.27 rnmol) was added to a solution of [4-[4-[(3S>3- methylmoipholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]phenyl]methanamine (100 mg, 0.27 mmol) in DCM (5 mL). Methanesulphonyl chloride (0.021 mL, 0.27 mniol) was added and the reaction stirred at room temperature for 2 hours. The organics were washed with water (5 mL), dried (MgSO4) and concentrated in vacuo. The crude material was purified on silica, eluting with 0-5% methanol in DCM, to give the desired material as a white solid (90 mg).
LCMS Spectrum: M+H+ 455; Retention Time 1.61 Method: Monitor Base NMR Spectrum: 1H NMR (400.132 MHz, CDCl3) δl.36 (d, 3H), 2.89 (s, 3H), 3.08 (s, 3H), 3.35 (m, IH), 3.60 (t, IH), 3.79 (m, 2H), 4.05 (d, IH), 4.18 (d, IH), 4.27 (s, 2H), 4.39 (d, 2H), 4.49 (s, IH), 4.80 (s, IH), 6.52 (s, IH), 7.43 (d, 2H), 8.36 (d, 2H). Test (a) average IC5O 4.5 μM.
The preparation of [4-[4-[(35)-3-methylmorpholin-4-yl]-6- (methylsulfonylmethyl)pyrimidin-2-yl]phenyl]methanamine is described below.
r4-r4-r('3y)-3-Methylmorpholin-4-yll-6-(methylsulfonylmethyl)pyrimidin-2- v 1] pheny 1] methanamine
Figure imgf000103_0002
2-ChloiO-4-[(35)-3-methylmoipholin-4-yl]-6-(methylsulfonylmethyl)pyrimidine (1.0 g, 3.27 minol) was dissolved in a solution of 18% DMF in a mixture of 7:3:2 DME:water:ethanol (9 mL). 4-Aminomethylphenyl boronic acid hydrochloride salt (0.92 g, 4.91 mmol), 2M sodium carbonate solution (3 mL) and dichloiObis(triphenylphospliine) palladium catalyst (115 mg, 0.16 mmol) were then added to the solution and refluxed at 900C for 16 hours under nitrogen atmosphere. The reaction was allowed to cool to room temp then partitioned between ethyl acetate and water. The organics were dried over magnesium sulphate, filtered and concentrated to dryness. The crude oil was chromatographed on silica, eluting with 0-5% methanol in DCM, to give the desired material as a cream solid (400 mg).
LCMS Spectrum: M-H" 375; Retention Time 1.58 Method: Monitor Base NMR Spectrum: 1H NMR (400.132 MHz, CDCl3) δl .36 (d, 3H), 3.08 (s, 3H), 3.34 (m, IH), 3.60 (m, IH), 3.75 (m, IH), 3.83 (d, IH), 3.94 (s, 2H), 4.05 (m, IH), 4.18 (m, IH), 4.26 (s, 2H), 4.49 (m, IH)5 6.50 (s, IH), 7.40 (d, 2H), 8.33 (d, 2H).
2-Chloro-4-[(3ιy)-3-methylmoiphoHn-4-yll-6-(methylsulfonylmethyl)pyrimidine
Figure imgf000104_0001
2,4-Dichloro-6-(methylsulfonylmethyl)pyrimidine (30 g, 0.13 mol) was dissolved in dichloromethane and stirred (under nitrogen) at -5°C. Triethylamine (17.4 mL, 0.13 mol) was added to give a clear brown solution. (35)-3-Methylmorpholine was dissolved in dichloromethane and added dropwise keeping the reaction below -5°C. The cooling bath was then removed and the mixture stirred for 1 hour. The reaction mixture was heated at reflux for 2 hours, then the reaction mixture was washed with water, dried then evaporated. The crude material was purified by preparative HPLC to give the desired material as a solid (19.3 g).
NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δl .21 - 1.23 (m, 3H), 3.11 (s, 3H), 3.19 - 3.26 (m, IH), 3.42 - 3.49 (m, IH), 3.58 - 3.62 (IH, m), 3.73 (d, IH), 3.92 - 3.96 (m, 2H), 4.27 - 4.31 (m, IH), 4.45 (s, 2H), 6.92 (s, IH) LCMS Spectrum: MH+ 306, retention time 1.42 min, Method 5 Min Acid The preparation of 2,4-dichloro-6-(methylsulfonylmethyl)pyrimidine was described earlier.
Example 6: iV-14-[4-[(3S)-3-Methyltiiorpholin-4-vU-6- (methvIsulfonvImethyl)pyrimidin-2-vHphenyllmethanesulfonaniide
Figure imgf000105_0001
2-ChloiO-4-[(35r)-3-methylmoipholin-4-yl]-6-(methylsulfonylmethyl)pyrimidine (150 mg, 0.49 mmol) was dissolved in a solution of 18% DMF in a mixture of 7:3:2 DME:water:ethanol (1.5 mL). 4-Aminomethylphenyl boronic acid hydrochloride salt (0.74 mmol), 2M sodium carbonate solution (0.5 mL) and dichlorobis(triphenylphosphine) palladium catalyst (18 mg, 0.02 mmol) were then added to the solution and refluxed at 90°C for 16 hours under nitrogen atmosphere. The reaction was allowed to cool to room temp then partitioned between ethyl acetate and water. The organics were dried over magnesium sulphate, filtered and concentrated to dryness. The crude solid was dissolved in DCM, insoluble impurities removed by filtration then the filtrate purified by prep HPLC to give the desired compound as a white solid (87 mg).
NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24 (3H, d), 2.93 (3H, s), 3.21 (3H, s), 3.24 (IH, m), 3.50 (IH, m), 3.65 (IH, m), 3.78 (IH, d), 3.98 (IH, m), 4.16 (IH, d), 4.43 (IH, s), 4.48 (2H, s), 6.76 (IH, s), 7.17 (2H, d), 8.21 (2H, d) LCMS Spectrum: M+H+ 441 ; Retention Time 1.45 Method: Monitor Acid Test (a) average IC50 1 μM.

Claims

1. A compound of formula (I)
Figure imgf000106_0001
formula (I) or a pharmaceutically acceptable salt thereof; wherein m is O, 1, 2, 3 or 4;
1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is CR8; X is a linker group selected from -CR4^CR5-, -CR4^CR5CR0R7-, -CR6R7CR5=CR4-, -CsC-, -C≡CCR6R7-, -CR°R7C≡C-, -NR4CR6R7-, -OCR0R7-, -SCR6R7-, -S(O)CR6R7-, -S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR0R7-, -NR4S(O)2CR6R7-, -S(O)2NR4CR0R7-, -C(O)NR4-, -NR4C(O)-, -NR4C(O)NR5-, -S(O)2NR4- and -NR4S(O)2-; R1 is a group selected from hydrogen, Ci-βalkyl, Co.galkenyl, C2.6alkynyl, carbocyclyl, carbocyclylC1-6alkyl, heterocyclyl and heterocyclylCi-βalkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R9, -OR9, -SR9, -SOR9, -SO2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2R10, -NR9CONR10R15, -NR9COCONR10R15 and -NR9SO2R10; R2 is a group selected from
Figure imgf000106_0002
carbocyclyl and heterocyclyl which group is substituted by -NR17SO2R18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R1 1, -OR1 1, -SR11, -SOR1 1, -SO2R1 1, -COR11, -CO2R11, -CONR11R12, -NR1 1R12, -NR11COR12, and -NR11COCONR12R16; each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -SR13, -SOR13, -SO2R13, -COR13, -CO2R13, -CONR13R14, -NR13R14, -NR13COR14, -NR13CO2R14 and -NR13SO2R14; R4 and R5 are independently hydrogen or Ci_6alkyl; or R1 and R4 together with the atom or atoms to which they are attached form a 5- to 10- membered carbocyclic or heterocyclic ring wherein 1 , 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, Ci.6alkoxy, haloCi- 6alkyl, haloCi-6alkoxy, hydro xyCi-6alkyl, hydroxyCi-όalkoxy, Ci-6alkoxyCi-6alkyl, Q- 6alkoxyCi.6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-ealkyl, (C1. 6alkyl)aminoCi-6alkyl, bis(Ci.balkyl)aminoCi-balkyl, cyanoCι-6alkyl, Ci-galkylsulfonyl, Ci- 6alkylsulfonylamino, Ci.6alkylsulfonyl(Ci-6alkyl)amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-όalkanoylamino, Ci.6alkanoyl(Ci-6alkyl)amino, carbamoyl, Ci- όalkylcarbamoyl and bis(Ci-όalkyl)carbamoyl;
R6 and R7 are independently selected from hydrogen, halo, cyano, nitro and Ci-balkyl; R8 is selected from hydrogen, halo, cyano and Ci,6alkyl;
R9 and R10 are independently hydrogen or a group selected from Ci-6alkyl, carbocyclyl, carbocyclylCi-6alkyl, heterocyclyl and heteiOcyclylCi-oalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-balkyl, Ci-6alkoxy, haloCi-t)alkyl, haloCi-6alkoxy,
Figure imgf000107_0001
Ci-6alkoxyCi-6alkyl, Ci.6alkoxyCi.6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci_6alkyl)aminoCi-6alkyl, bis(C1-6alkyl)aminoCi.6alkyl, cyanoCi-6alkyl, Ci.6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-6alkylsulfonyl(Ci.6alkyl)amino, sulfamoyl, Ci-6alkylsulfamoyl, Hs(Ci -όalkyl)sulfamoyl, Ci-6alkanoylamino, C1-balkanoyl(Ci. 6alkyl)amino, carbamoyl, Ci-όalkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R11, R12 and R17 are independently hydrogen or a group selected from Ci^alkyl, carbocyclyl, carbocyclylCi-ealkyl, heterocyclyl and heterocyclylCi-6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci.6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy,
Figure imgf000107_0002
hydroxyCi.6alkoxy, Ci-6alkoxyCi.6alkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-balkyl)amino, aminoCi.6alkyl, (Ci-6alkyl)aminoCi-balkyl, bis(Ci-6alkyl)aminoCi. 6alkyl, cyanoC[-6alkyl, Ci-balkylsulfonyl, Ci-6alkanoylamino, Ci.6alkanoyl(Ci_ 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R13, R14, R15, R16 and R18 are independently hydrogen or a group selected from Ci-6alkyl, carbocyclyl, carbocyclylCi-6alkyl, heterocyclyl and heterocyclylCi-ealkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro. hydroxy, C1.5alk.yl, Ci-ealkoxy, haloCi_6alkyl, haloCi-6alkoxy; hydiOxyCi-6alkyl, hydroxy C i-6alkoxy, Ci-6alkoxyCi-6alkyl5 Ci-όalkoxyCi-όalkoxy, amino, Ci.όalkylamino, bis(Ci-6alkyl)amino, aminoCi.6alkyl, (C[.6alkyl)aminoCi.6alkyl, bis(Ci_6alkyl)aminoCi- ealkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-6alkylsulfonyl(Ci- 6alkyl)amino, sulfamoyl, Ci.6alkylsulfamoyl, bis(Ci-6alkyl)sυlfamoyl, Ci-όalkanoylamino, Ci.6alkanoyl(Ci-6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(C1_ 6alkyl)carbamoyl.
2. A compound, or a pharmaceutically acceptable salt thereof, according to Claim 1 wherein the compound of formula (I) is a compound of formula (Ia) or (Ib)
Figure imgf000108_0001
(Ia) (Ib) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, X5 Y1 and Y2 are as defined for the compound of formula (I) as claimed in Claim 1.
3. A compound, or a pharmaceutically acceptable salt thereof, according to Claim 1 or 2 wherein R3 is methyl.
4. A compound, or a pharmaceutically acceptable salt thereof, according to any one of Claims 1 to 3 wherein Y1 is CR8 and Y2 is N.
5. A counpound, or a pharmaceutically acceptable salt thereof, according to Claim 4 wherein Y1 is CH and Y2 is N.
6. A compound, or a pharmaceutically acceptable salt thereof, according to any one of Claims 1 to 5 wherein X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-, -S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)NR5CR6R7-, -S(O)2NR4CR6R7, -C(O)NR4- and -NR4C(O)-.
7. A compound, or a pharmaceutically acceptable salt thereof, according to Claim 6 wherein X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-,
-S(O)CR6R7-, -S(O)2CR6R7-, -C(O)NR4-, and -NR4C(O)-.
8. A compound, or a pharmaceutically acceptable salt thereof, according to Claim 7 wherein X is a linker group selected from -NR4CH2-, -OCH2-, -OCH(CH3)-, -OC(CH3)2-, -SCH2-, -SCH(CH3)-, -SC(CH3V, -S(O)CH2-, -S(O)CH(CH3)-, -S(O)C(CH3)2-, -S(O)2CH2-, -S(O)2CH(CH3)-, -S(O)2C(CHs)2-, -C(O)NR4- and -NR4C(O)-.
9. A compound, or a pharmaceutically acceptable salt thereof, according to Claim 8 wherein X is -S(O)2CH2-, -S(O)2CH(CH3)- or -S(O)2C(CH3)2-.
10. A compound, or a pharmaceutically acceptable salt thereof, according to any one of Claims 1 to 9 wherein R1 is a group selected from adamantyl, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, pyrazolylethyl, furanylmethyl, furanylethyl, thienylmethyl, thienylethyl, pyridinylmethyl, pyiϊdinylethyl, pyrimidinylmethyl, pyrimidinylethyl, pyrazinylmethyl and pyrazinylethyl, which group is optionally substituted by 1 , 2 or 3 substituent group selected from halo, cyano, nitro, R9, - OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10.
11. A compound, or a pharmaceutically acceptable salt thereof, according to Claim 10 wherein R1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONH2 and -CONHCH3.
12. A compound, or a pharmaceutically acceptable salt thereof, according to Claim 1 1 5 wherein R1 is a group selected from methyl, isopropyl, cyclopropyl, cyclohexyl,
-CH2CH2OH, -CH2CH2NC(O)CH3, phenyl, 4-fluorophenyl, 2-chlorophenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 2-methylphenyl, 4-acetamidophenyl, 4-aminophenyl, , pyridin-4-yl, pyridin-2-yl, 2-oxopyrolidin-3-yl,, thiazol-2-yl, 4-methylthiazol-2-yl, and 3-methyl-l,3,4-thiadiazol-2-yl.
10
13. A compound, or a pharmaceutically acceptable salt thereof, according to Claim 12 wherein R1 is methyl.
14. A compound, or a pharmaceutically acceptable salt thereof, according to any one is of Claims 1 to 13 wherein R2 is selected from 5 or 6 membered carbocyclyl or heterocyclyl which group is substituted by -NR17SO2R18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR1 1, -COR11, -CONR1 1R12, -NR11R12 and -NR1 1COR12.
20 15. A compound, or a pharmaceutically acceptable salt thereof, according to Claim 14 wherein R2 is selected from a 6 membered aryl and 5 or 6 membered heteroaryl which group is substituted by -NR17SO2R18 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, -NR1 1R12 and -NR11COR12.
25
16. A compound, or a pharmaceutically acceptable salt thereof, according to Claim 15 wherein R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is substituted by -NR17SO2R18 and optionally substituted by one or more substituent group independently selected from 30 halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, -NR11R12 and -NR11COR12.
17. A compound, or a pharmaceutically acceptable salt thereof, according to Claim 16 wherein R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is substituted by -NR17SO2R18 and optionally substituted by one or more substituent group independently selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON(CH3)2.
18. A compound, or a pharmaceutically acceptable salt thereof, according to Claim 17 wherein R2 is phenyl or pyiϊdyl substituted by -NR17SO2R18 and optionally substituted by one or more substituent group independently selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON(CH3)2.
19. A compound, or a pharmaceutically acceptable salt thereof, according to Claim 18 wherein R2 is
Figure imgf000111_0001
wherein A1 and A2 are selected from CH or N provided that at least one of A1 or
A2 is CH.
20. A compound, or a pharmaceutically acceptable salt thereof, according to any one of Claims 14 to 19 wherein R17 is hydrogen.
21. A compound, or a pharmaceutically acceptable salt thereof, according to any one of Claims 1 to 20 wherein R18 is hydrogen or a group selected from Ci.6alkyl, C3- 6cycloakyl, aryl, heteroaryl, arylCi-dalkyl and heteroarylCi-6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, Ci-6alkoxy, haloCi.ealkyl, haloCi-6alkoxy, hydroxy C l-βalkyl, hydroxyCi-6alkoxy,
Figure imgf000111_0002
Ci-6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci-oalkyl)amino, aminoCi-6alkyl, (Ci-6alkyl)aniinoCi.6alkyl, bis(Ci-6alkyl)aminoCi. 6alkyl, cyanoCi-δalkyl, C|.6alkylsulfonyl, Ci-6alkylsulfonylamino, C|-6alkylsulfonyl(Ci. 6alkyl)amino, sulfamoyl, Ci.όalkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-ealkanoylamino, Ci-6alkanoyl(Ci-6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and Hs(Ci- 6alkyl)carbamoy 1.
22. A compound, or a pharmaceutically acceptable salt thereof, according to Claim 21 wherein R18 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i- butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazoylmethyl, isoxazolyl, pyrazolyl, pyridinyl and pyrimidinyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Cι-6alkyl, Ci-ealkoxy, haloCi-ealkyl, haloCi^alkoxy, hydroxyCi-ealkyl, hydroxyCi-ealkoxy, Ci.6alkoxyCi.6alkyl, Ci.6alkoxyCi.6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-ealkyl, (Ci-δalkyOaminoCi-όalkyl, bis(Ci-6alkyl)aminoCi. όalkyl, cyanoCi.όalkyl,
Figure imgf000112_0001
Ci.δalkylsulfonylamino, Ci-balkylsulfonyl(Cι- 6alkyl)amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-όalkanoylamino, Ci-tlalkanoyl(Ci-6alkyl)amino, carbamoyl, C1-6alkylcarbamoyl and bis(Ci- 6alkyl)carbamoyl.
2 1.2. A compound, or a pharmaceutically acceptable salt thereof, according to Claim 22 wherein R18 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i- butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
-CH2(cyclopropyl), -CH2CH2NMe2, -CH(CH3)CH2OH, -C(CH3)2CH2OH, -CH2CH2OH5 -CH2CH2CH2OH, 4-methylphenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4- fluorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, thien-2-yl, -CH2(imidazol-2-yl), -CH2(imidazol-3-yl), isoxazolyl-3-yl, 6-oxo-lH-pryrdin-2-yl, 5-methylisoxazol-3-yl, 1 -methylρyrazol-4-yl, 6-methoxypryridin-3-yl, 5-fluoropyridin-2-yl, pyrimidin-2-yl, and lH-pyrazol-3-yl.
24. A compound, or a pharmaceutically acceptable salt thereof, according to Claim 23 wherein R18 is hydrogen or a group selected from methyl, ethyl, propyl, butyl, cyclopropyl, and 4-fluorophenyl.
25. A compound, or a pharmaceutically acceptable salt thereof, according to Claim 1 selected from any one of the Examples, or a pharmaceutically acceptable salt thereof.
26. A compound of formula (I) or a pharmaceutically acceptable salt thereof according 5 to any one of Claims 1 to 25 for use as a medicament in the treatment of proliferative disease.
27. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of Claims 1 to 25 in the manufacture of a medicament for use in the io treatment of proliferative disease.
28. The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined in any one of Claims 1 to 25 for the production of an antiproliferative effect in a warm-blooded animal such as man.
15
29. The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined in any one of Claim 1 to 25 in the manufacture of a medicament for use in the production of an anti-pro lifer ative effect in a warm-blooded animal such as man.
20 30. A method for producing an antiproliferative effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I)5 or a pharmaceutically acceptable salt thereof, as defined in any one of Claims 1 to 25.
25 31. A method for treating cancer, inflammatory diseases, obstructive airways diseases, immune diseases or cardiovascular diseases in a warm blooded animal such as man that is in need of such treatment which comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined in any one of Claims 1 to 25.
30
32. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of Claims 1 to 25, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier.
33. A compound of formula (I) as defined in any one of Claims 1 to 25, or a pharmaceutically acceptable salt thereof, for use as a medicament.
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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009007750A1 (en) * 2007-07-09 2009-01-15 Astrazeneca Ab Morpholino pyrimidine derivatives used in diseases linked to mtor kinase and/or pi3k
WO2010073034A1 (en) 2008-12-22 2010-07-01 Astrazeneca Ab Pyrimidine indole derivatives for treating cancer
US7750003B2 (en) 2006-08-24 2010-07-06 Astrazeneca Ab Compounds-943
WO2011025889A1 (en) 2009-08-28 2011-03-03 Takeda Pharmaceutical Company Limited HEXAHYDROOXAZINOPTERINE COMPOUNDS FOR USE AS mTOR INHIBITORS
WO2011092197A1 (en) * 2010-01-26 2011-08-04 Boehringer Ingelheim International Gmbh 5-alkynyl pyrimidines and their use as kinase inhibitors
US8097622B2 (en) 2008-10-14 2012-01-17 Daiichi Sankyo Company, Limited Morpholinopurine derivatives
WO2012099581A1 (en) 2011-01-19 2012-07-26 Takeda Pharmaceutical Company Limited Dihydrofuropyrimidine compounds
US8252802B2 (en) 2010-06-11 2012-08-28 Astrazeneca Ab Chemical compounds
WO2012148548A1 (en) 2011-02-25 2012-11-01 Takeda Pharmaceutical Company Limited N-substituted oxazinopteridines and oxazinopteridinones
WO2014011568A1 (en) 2012-07-10 2014-01-16 Takeda Pharmaceutical Company Limited Azaindole derivatives which act as pi3k inhibitors
US8633183B2 (en) 2010-01-26 2014-01-21 Boehringer Ingelheim International Gmbh 5-alkynyl-pyrimidines
EP2762142A1 (en) 2009-10-30 2014-08-06 ARIAD Pharmaceuticals, Inc. Compositions for treating cancer
US8916548B2 (en) 2008-07-29 2014-12-23 Boehringer Ingelheim International Gmbh 5-alkynyl-pyrimidines
WO2015106012A1 (en) 2014-01-09 2015-07-16 Takeda Pharmaceutical Company Limited Azaindole derivatives
WO2015106014A1 (en) 2014-01-09 2015-07-16 Takeda Pharmaceutical Company Limited Azaindole derivatives
US10683293B2 (en) 2014-08-04 2020-06-16 Nuevolution A/S Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases
US11447479B2 (en) 2019-12-20 2022-09-20 Nuevolution A/S Compounds active towards nuclear receptors
US11613532B2 (en) 2020-03-31 2023-03-28 Nuevolution A/S Compounds active towards nuclear receptors
US11780843B2 (en) 2020-03-31 2023-10-10 Nuevolution A/S Compounds active towards nuclear receptors
US12441704B2 (en) 2019-12-20 2025-10-14 Nuevolution A/S Compounds active towards nuclear receptors

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002038551A1 (en) * 2000-11-10 2002-05-16 F. Hoffman-La Roche Ag Pyrimidine derivatives and their use as neuropeptide y receptor ligands
EP1277738A1 (en) * 2000-04-27 2003-01-22 Yamanouchi Pharmaceutical Co. Ltd. Condensed heteroaryl derivatives
WO2004048365A1 (en) * 2002-11-21 2004-06-10 Chiron Corporation 2,4,6-trisubstituted pyrimidines as phosphotidylinositol (pi) 3-kinase inhibitors and their use in the treatment of cancer
WO2006005915A1 (en) * 2004-07-09 2006-01-19 Astrazeneca Ab 2, 4, 6-trisubstituted pyrimidines as phosphotidylinositol (pi) 3-kinase inhibitors and their use in the treatment of cancer
WO2006005918A1 (en) * 2004-07-09 2006-01-19 Astrazeneca Ab 2, 4,6-trisubstituted pyrimidines as phosphotidylinositol (pi) 3-kinase inhibitors and their use in the treatment of cancer
WO2006053227A2 (en) * 2004-11-10 2006-05-18 Synta Pharmaceuticals Corp. Il-12 modulatory compounds
WO2006124662A1 (en) * 2005-05-13 2006-11-23 Synta Pharmaceuticals Corp. Il-12 modulatory compounds
WO2006125554A1 (en) * 2005-05-27 2006-11-30 Bayer Healthcare Ag Use of cyanopyrimidines for the treatment of cardiovascular diseases
WO2007042806A1 (en) * 2005-10-11 2007-04-19 Ludwig Institute For Cancer Research Pyrimidine derivatives for the treatment of cancer

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3922735A1 (en) * 1989-07-11 1991-01-24 Hoechst Ag AMINOPYRIMIDINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, THE AGENTS CONTAINING THEY AND THEIR USE AS FUNGICIDES
US7772271B2 (en) * 2004-07-14 2010-08-10 Ptc Therapeutics, Inc. Methods for treating hepatitis C
AU2006284751A1 (en) * 2005-09-01 2007-03-08 Array Biopharma Inc. Raf inhibitor compounds and methods of use thereof

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1277738A1 (en) * 2000-04-27 2003-01-22 Yamanouchi Pharmaceutical Co. Ltd. Condensed heteroaryl derivatives
WO2002038551A1 (en) * 2000-11-10 2002-05-16 F. Hoffman-La Roche Ag Pyrimidine derivatives and their use as neuropeptide y receptor ligands
WO2004048365A1 (en) * 2002-11-21 2004-06-10 Chiron Corporation 2,4,6-trisubstituted pyrimidines as phosphotidylinositol (pi) 3-kinase inhibitors and their use in the treatment of cancer
WO2006005915A1 (en) * 2004-07-09 2006-01-19 Astrazeneca Ab 2, 4, 6-trisubstituted pyrimidines as phosphotidylinositol (pi) 3-kinase inhibitors and their use in the treatment of cancer
WO2006005918A1 (en) * 2004-07-09 2006-01-19 Astrazeneca Ab 2, 4,6-trisubstituted pyrimidines as phosphotidylinositol (pi) 3-kinase inhibitors and their use in the treatment of cancer
WO2006053227A2 (en) * 2004-11-10 2006-05-18 Synta Pharmaceuticals Corp. Il-12 modulatory compounds
WO2006124662A1 (en) * 2005-05-13 2006-11-23 Synta Pharmaceuticals Corp. Il-12 modulatory compounds
WO2006125554A1 (en) * 2005-05-27 2006-11-30 Bayer Healthcare Ag Use of cyanopyrimidines for the treatment of cardiovascular diseases
WO2007042806A1 (en) * 2005-10-11 2007-04-19 Ludwig Institute For Cancer Research Pyrimidine derivatives for the treatment of cancer

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
"4-PYRIMIDINECARBOXAMIDE, 2,6-DI-4-MORPHOLINYL-N-(2-PHENYLETHYL)-", CHEMCATS, 2004, XP002348927 *
CHANDRA N ET AL: "Antileishmanial agents part-IV: synthesis and antileishmanial activity of novel terpenyl pyrimidines", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, EDITIONS SCIENTIFIQUE ELSEVIER, PARIS, FR, vol. 40, no. 6, June 2005 (2005-06-01), pages 552 - 556, XP004911366, ISSN: 0223-5234 *
DOTZAUER ET AL: "2,4-Diamino-9H-pyrimido[4,5-b]indol-5-ols: Synthesis, in vitro cytotoxic activity, and QSAR investigations", BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER SCIENCE LTD, GB, vol. 14, no. 21, 1 November 2006 (2006-11-01), pages 7282 - 7292, XP005661674, ISSN: 0968-0896 *
KATIYAR S B ET AL: "Syntheses of 2,4,6-trisubstituted pyrimidine derivatives as a new class of antifilarial topoisomerase II inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 15, no. 1, 3 January 2005 (2005-01-03), pages 47 - 50, XP004668747, ISSN: 0960-894X *
KUMAR ET AL.: "A Novel and Convenient Synthesis of 2-Amino-4-(N-alkyl-N-arylamino)-pyrimidines using Polarized Ketene S,S- and S,N-Acetals", SYNTHESIS, vol. 9, 1980, pages 748 - 751, XP002432317 *
SCHMIDT R R: "NEUE SYNTHESE VON PYRIMIDINDERIVATEN", CHEMISCHE BERICHTE, VERLAG CHEMIE GMBH. WEINHEIM, DE, vol. 98, no. 2, 1965, pages 346 - 351, XP009042438, ISSN: 0009-2940 *
SPITZNER ET AL.: "Ringschlussreaktionen von 2-Acyl-1-chlor-enaminen mit thioamidfunktionellen Verbindungen: Wahlweiser Zugang in die 1,3-Thiazin- und 1,3-Oxazin-Reihe", MONATSHEFTE FÜR CHEMIE, vol. 118, 1987, pages 1383 - 1394, XP009083062 *

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